COVALENTLY CROSS-LINKED OLIGONUCLEOTIDES

Abstract: Covalent cross-linkages for two oligonucleotide strands or for first and second regions of a single oligonucleotide strand connect sugar moieties of nucleotides on the respective strands or the regions of the single strand. The cross-linkages are connected to at least one strand or region via a space-spanning group. The cross-linkage also can be connected to the other strand or other region via a space-spanning group or via an abasic site located on the other strand or other region.

Description: COVALENTLY CROSS-LINKED OLIGONUCLEOTIDES FIELD OF THE INVENTION This invention is directed to covalent cross-linkages for oligonucleotides. The cross-linkages connect either two oligonucleotide strands or different regions of a single oligonucleotide strand via a space-spanning group that extends from a sugar moiety on a nucleotide of the first strand or strand region to a nucleotide on the other strand or strand region. BACKGROUND OF THE INVENTION Several examples have been reported of cross-linking between complementary oligonucleotides. The purpose of such cross-linking often has been to disrupt the function of a nucleic acid, primarily by cleavage of the target. It is known to cross-link nucleic acids in a positionally uncontrolled manner with UV exposure. However, Grineva, and Karpova, FEBS. , 1973, 32, 351-355, appear to have been the first to covalently cross-link complementary strands of oligonucleotides at a specific site utilizing controlled chemistry. A nitrogen mustard was attached to the 3' terminal ribose unit of an oligonucleotide via an acetal linkage or to the 5' end of an oligonucleotide via a phosphoramide linkage. On hybridization, the reactive mustards covalently cross-linked to the complemen- tary strand via alkylation of the ternary heteroaromatic nitrogen atom at the 7-position of guanine or adenine. However, the alkylated base thus formed is a quaternary charged species that is subject to rapid chemical degradation via imidazole ring opening followed by cleavage of the targeted strand. Enzymes are known to remove alkylated bases from nucleic acids. Indeed, such enzymatic removal is implicated in DNA repair mechanisms. The destruction of a targeted alkylated nucleic acid theoretically could be utilized for antimicrobial or antitumor therapy. However, cross-linking alkylation reactions and subsequent degradations are not desirable where host cell viability is necessary. Summerton and Bartlett have proposed another type of alkylated oligonucleotide wherein an α-bromomethylketone attached to the -position of a cytidine nucleotide spans the major groove and alkylates the 7-position of a complementary guanine residue in a targeted strand. [See, J " . Mol . Biol . , 1978, 122, 145-162; J " . Theor. Biology, 1979, 78, 61-75; and United States Patent 4,123,610] . As with the .nitrogen mustards noted above, this alkylation yields a charged species that effects cleavage of the targeted nucleic acid strand following alkylation. A further example of a covalent cross-linkage to the 7-position nitrogen of guanine is described by Meyer et. al . , J. Am. Chem. Soc , 1989, 111, 8517. The authors attached an iodoacetamidopropyl moiety to the 5-position of a thymidine nucleotide of DΝA. The iodoacetamidopropyl moiety subsequently alkylated the 7-position of a guanine nucleotide at a position two base pairs down the complementary strand. Cleavage of the targeted strand was observed at various times and temperatures. Matteucci and Webb have described a hybridization triggered cross-linking process where an Ν6 , N6-ethano- adenine or N4,N4-ethanocytosine alkylates an appropriately positioned nucleophile in a complementary strand. [See, Nucleic Acids Res. , 1986, 14 , 7661; Tetrahedron Letters, 1987, 28, 2469-2472.] This process has been designed to inactivate the normal .function of the targeted DNA either by forming a stable adduct or by hydrolytic or enzymatic cleavage. A cross-linkage similar to the above-noted N6,N6- ethano linkage was described by Ferentz, et al . , J. Am. Chem. Soc , 1991, 113 , 4000, who utilized either an ethyl disulfide or a propyl disulfide linkage to connect the N6-positions of adenine residues on a self-complementary oligonucleotide. Λ Lee, et al . , Biochemistry, 1988, 27, 3197-3203, * f 5 described the interaction of psoralen-derivatized methyl phosp- , κ ' honate oligonucleotides with single-stranded DNA. According to this method, irradiation effects cross-linking which, in turn, inactivates DNA. Psoralen cross-linkages occur only between pyrimidine bases to join single-stranded or, more commonly, 10 double-stranded structures. The generation of an abasic site on a nucleic acid has been implicated in the above-noted enzymatic removal of alkylated bases from nucleic acids. Manoharan, et al . , J. Am. Chem. Soc , 1987, 109, 7217 and Manoharan, et al . , J. Am . Chem . 15 Soc , 1988, 110, 2690, have characterized abasic sites in oligonucleotides utilizing 13 C NMR spectroscopy. Abasic sites also have been created on nucleic acids to attach the inter- calator 9-aminoellipticine to nucleic acids. Vasseur, et al . , Nucleosides & Nucleotides, 1989, 8, 863-866, reported that the 20 trimer Tp(Ap)Pt, where (Ap) is an apurinic site yielded a mixture of products when reacted with the intercalator 9- aminoellipticine. The reaction produced a desired Schiff's base adduct between the apurinic site and the 9- aminoellipticine, but also resulted in cleavage of the 25 phosphate backbone. This work was extended by Bertrand, et al . , Nucleic Acids Research, 1989, 17, 10307, to the interaction of 9-aminoellipticine and a 13-mer oligonucleotide. The 13-mer oligonucleotide contained only a single purine nucleotide. Acid treatment resulted in loss of the purine base 30 to yield an unstable abasic site. The 9-aminoellipticine was successfully linked to the abasic site in the oligonucleotide by reducing the Schiff's base adduct during the reaction. «•-.. Using an oligonucleotide having a single purine site, the Λ authors, were able to study the coupling of the intercalator 9- < * * 35 aminoellipticine to the oligonucleotide. It is unlikely, however, that oligonucleotides which bind to sequences of biological significance contain only a single purinic site. Other abasic site-containing oligonucleotides have been assembled by synthetically incorporating abasic nucleoside precursors into an oligonucleotide. For example, Philippe, et al . , Tetrahedron Letters, 1990, 31 , 6347-6350, incorporated a 2-deoxy-D-ribose having a primary amide function attached via a pentamethylene chain to its 1' -position. 1,2-Dideoxy-D-ribo- furanose and butane 1,3-diol likewise have been incorporated into oligonucleotides. [See, P.Iyer, et al . , Nucleic Acids Research, 1990, 18, 2855.] Groehke, et al . , Helvetica Chimica Acta, 1990, 73 , 608, reported the preparation of a (tert-butyl)dimethylsilyl- protected deoxy-D-ribose and its incorporation into oligo¬ nucleotides utilizing solid state techniques. Reoc'h, et al . , Tetrahedron Letters, 1991, 32, 207, used 1- (o-nitrobenzyl) -2- deoxy-D-ribofuranose in the synthesis of other oligonuc¬ leotides. None of these chemically generated abasic sites have been utilized to effect cross-linking. Application PCT/US91/01822, filed March 19, 1991 and entitled Reagents And Methods For Modulating Gene Expression Through RNA Mimicry, discloses effective use of oligonucleotides that mimic RNA structure. The entire disclosure Application PCT/US91/01822, which is assigned to the assignee of this application, is herein incorporated by reference. The oligonucleotides disclosed in PCT/US91/01822 are selected to mimic a portion of an RNA encoded by a gene. The RNA-mimicking oligonucleotides interfere with or modulate gene expression by interfering with protein-RNA interactions. In order to mimic an RNA, an oligonucleotide must assume and retain the RNA's secondary and tertiary structure. Although the physical and chemical forces that normally retain the RNA in its secondary and tertiary structure are non- covalent in nature, one way to fix an RNA mimic in the necessary secondary and tertiary structure would be to covalently cross-link the mimic. However, presently-known techniques for cross-linking nucleic acid strands either lead to strand cleavage, disruption of structure or Watson/Crick hydrogen bonding, or are only useful for limited, specific sequences or at specific locations in a sequence. Cross-linkages between two oligonucleotide strands or between regions of a single strand would be undesirable where the cross-linkages could destroy the strands or strand or could unduly modify the conformational structure of the oligonu¬ cleotide. Cross-linkages also would be undesirable where they do not allow the cross-linked product to approximate the conformation of natural nucleic acids. Heretofore, there has be no suggestions in the art of cross-linkages or methods of cross-linking that do not destroy the strands, that allow suitable conformations, that are useful on various sequences and at various positions within the sequences, and that allow normal ranges of features such as the "tilt" and "propeller twist" features found in naturally occurring nucleic acid duplexes. Accordingly there remains a long-felt need for nucleic acid cross-linkages and methods of cross-linking nucleic acids. OBJECTS OF THE INVENTION It is a primary object of this invention to provide improved covalently cross-linked nucleic acids and methods of forming the same. It is a further object of this invention to provide individual oligonucleotide strands that are covalently bonded to one another at one or more sites on the strands. It is an even further object of this invention to provide a single oligonucleotide strand that is covalently bonded to itself at one or more sites on the strand. It is an even further object of this invention to provide RNA mimics that are fixed in specific spatial conformations via cross-linking covalent bonds. It is an additional object of this invention to provide covalently cross-linked oligonucleotides that have the same sequence as known nuclease-resistant mimics of binding receptors for nucleic acid-binding proteins. These and other objects of this invention will become apparent to those skilled in the art from a review of this specification and the claims appended hereto. BRIEF DESCRIPTION OF THE INVENTION In accordance with this invention there are provided sequence-specific, covalently cross-linked nucleic acids comprising a first nucleotide located either on a first strand of complementary oligonucleotide strands or on a single oligo¬ nucleotide strand. The cross-linked nucleic acids further comprise a second nucleotide located on a further strand of the complementary strands or on the single strand at a site distal to the first nucleotide. A first bond means is located on a sugar moiety of the first nucleotide and a second bond means is located on a sugar moiety of the second nucleotide. A covalent cross-linkage connects the first and the second bond means and, in doing so, cross-links the strand or strands. In one embodiment of the invention, the first and the second nucleotides are located within first and second nucleotide sequences, respectively, on a single oligonucleotide strand. In a first preferred embodiment, the second-nucleotide sequence is separated from the first nucleotide sequence by a distance that allows the oligonucleotide strand to assume a conformation wherein the first and second nucleotide sequences are specifically hybridizable with one another. In a further preferred embodiment, the first and the second nucleotides are located in non-hybridizable positions but are in sufficient proximity to allow cross-linking between the first and second nucleotides. In a preferred embodiment of the invention, the first bond means includes an abasic site and the second bond means includes a space-spanning group that, in turn, includes an active functional group that is capable of covalently bonding with the abasic site. Further in accordance with the invention there are provided sequence-specific, cross-linked oligonucleotides that include a first nucleotide located on a first complementary oligonucleotide strand, a second nucleotide located on a second complementary strand, a first bond precursor located on a sugar moiety of the first nucleotide, a second bond precursor located on a sugar moiety of the second nucleotide, and a covalent cross-linkage connecting the first and the second bond precursors to cross-link the first and the second strands. In a preferred embodiment of the invention, the first nucleotide is located in a first nucleotide sequence, the second nucleotide is located in a second nucleotide sequence, and the second nucleotide sequence is complementary to and specifically hybridizable with the first nucleotide sequence. Additionally in accordance with this invention there are provided sequence-specific, cross-linked oligonucleotides that include a first nucleotide located on an oligonucleotide strand and a second nucleotide located on the same oligonucleotide strand. The first and second nucleotides are separated by a distance that allows the nucleotides to specifically hybridize with one another. A first bond precursor is located on a sugar moiety of the first nucleotide and a second bond precursor is located on a sugar moiety of the second nucleotide. A covalent cross-linkage connects the first and the second bond precursors, cross-linking the first and second nucleotides. In a preferred embodiment, the first nucleotide is located in a first nucleotide sequence, the second specific nucleotide is located in a second nucleotide sequence, and the second nucleotide sequence is complementary to and hybridizable with the first nucleotide sequence. In a further preferred embodiment, the first and second nucleotides are located in nonhybridizable positions but are in sufficient proximity that a cross-linkage can be formed between them. Also in accordance with this invention there are provided cross-linked oligonucleotides comprising a first sequence region that includes an abasic site and a second sequence region that includes a space-spanning group. An active functional group is located on the space-spanning group and is covalently coupled with the abasic site. In a first preferred embodiment, the first sequence region and the second sequence region are on the same oligonucleotide strand. In a further preferred embodiment, the first sequence region and the second sequence region are on different oligonucleotide strands. In these preferred embodiments, the first sequence r- egion and the second sequence region are complementary to and specifically hybridizable with one another. Preferably, the active functional group is an amine, hydrazine, hydroxylamine, semicarbazide, thiosemicarbazide, hydrazide, thiol or alcohol, and the abasic site includes an aldehydic functionality. Space-spanning groups according to the invention comprise elongated chains from about 1 to about 50 atoms in length. Space-spanning groups preferably comprise elongated chains from about 4 to about 20 atoms in length, more preferably chains from about 8 to about 13 atoms in length. Further in accordance with this invention there are provided cross-linked oligonucleotides that include a first sequence region, a second sequence region, and a covalently bonded linker of the structure: wherein X x is covalently connected to the first sequence region and X 2 is covalently connected to the second sequence region and where: (i) X x and X 2 , independently, are 0, S, NH, CH 2 or CO; L x and L 2 , independently, are C X -C 2Q straight chain alkyl, C j^ -C^ straight chain substituted alkyl, C 2 -C 3o branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted - alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, polyether, aryl, aralkyl or heterocyclic; and Y is an imine, amine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide-hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal, thiohemiacetal, α-keto-alkylthioalkyl or α-keto-alkylaminoalkyl; or (ii) X- L and X 2 , independently, are 0 or NH; and L x -Y-L 2 together are NH-L 3 -NH or NH-NH-L 3 -NH-NH; and L 3 is C 1 -C 20 straight chain alkyl, C 1 -C 20 straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, polyether, aryl, aralkyl or heterocyclic; or (iii) X 1 and X 2 , independently, are O, S, NH, CH 2 or CO; L-_ and L 2 , independently, are C^C^ straight chain alkylamino, C 1 -C 20 straight chain substituted alkylamino, C 2 -C 50 branched chain alkylamino, C 2 -C 50 branched chain substituted alkylamino, C 2 -C 20 straight chain alkenylamino, C 2 -C 20 straight chain substituted alkenylamino, C 3 -C 50 branched chain alkenylamino, C 3 -C 50 branched chain substituted alkenylamino, C 2 -C 20 straight chain alkynylamino, C 2 -C 20 straight chain substituted alkynylamino, C 3 -C 5Q branched chain alkynylamino, C 3 -C 50 branched chain substituted alkynylamino, C^C^ straight chain alkylthio, C- L -C^ straight chain substituted alkylthio, C 2 -C 50 branched chain alkylthio, C 2 -C 50 branched chain substituted alkylthio, C 2 -C 20 straight chain alkenylthio, C 2 -C 20 straight chain substituted alkenylthio, C 3 -C 50 branched chain alkenylthio, C 3 -C S0 branched chain substituted alkenylthio, C 2 -C 20 straight chain alkynylthio, C 2 -C 20 straight chain substituted alkynylthio, C 3 -C 50 branched chain alkynylthio or C 3 -C 50 branched chain substituted alkynylthio; and Y is a heterobifunctional or homobifunctional cross-linking reagent; where said substituent of said substituted alkyl, substituted alkenyl and substituted alkyne moieties is an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that enhances the ■ pha * rmacodynamic properties of oligonucleotides or a group that enhances the pharmacokinetic properties of oligonucleotides. Further in accordance with this invention there are provided cross-linked oligonucleotides that individually include a first sequence region, a second sequence region, a first space-spanning group connected to a 2'-position of a nucleotide located in the first sequence region, a second space-spanning group connected to a 2'-position of a 'nucleotide in the second sequence region, and a linking moiety covalently connecting the first and second space-spanning groups. In preferred embodiments the linking moiety is: -N=CH-, -N(R)-, -N(R) -CH 2 -N(R) -, -0-N=CH-, -O-N(R) -, -N(R) -N(R) -, -N(R) -N=CH-, -HC=N-N=CH-, -C(0)-N(R)-N=CH-, -C(0)N(R)-, -C(O) -N(R) -N(R) -, -N(R) -C(0) -N(R) -N(R) -, -N(R) -C(Q) -N(R) -N(R) =CH-, -N(R) -C(S) -N(R) -N(R) -, -N(R) -C(S) -N(R) -N(R)=CH-, -CH(OH) -0-CH 2 -, -CH(OH) -S-CH 2 -, -CH 2 -S-CH 2 -C(0) -CH 2 -, -CH 2 -NH-CH 2 -C(0) -CH 2 - or -S-S-; wherein R is H, alkyl, alkenyl, aralkyl, an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that - enhances the pharmacodynamic properties of oligonucleotides or a group that enhances the pharmacokinetic properties of oligonucleotides. Further in accordance with this invention there are provided methods for fixing a sequence-specific oligonucleotide in a set configuration. Such methods include selecting a first site in the oligonucleotide, said first site having a first nucleotide sequence. The methods further include selecting a second site in the oligonucleotide, said second site having a second nucleotide sequence. A first bond precursor is attached to a sugar moiety of a first nucleotide of the first site, while a second bond precursor is attached to a sugar moiety of a second nucleotide of the second site. A covalent cross- linkage is formed between the first and the second bond precursors. In a preferred embodiment, the first bond pre¬ cursor is attached to the first site by reacting a first nucleotide precursor with a reagent for introducing the first bond precursor on a sugar moiety of the first nucleotide precursor. The first nucleotide precursor is derivatized to a protected and activated form and is synthetically incorporated into the first specific nucleotide sequence. The second nucleotide sequence can be complementary to and hybridizable with the first nucleotide sequence. In one embodiment of this method, the first bond precursor is an abasic nucleotide and the second bond precursor is attached to a 2'-position of the second nucleotide. In this embodiment, the second bond precursor is reacted -with the abasic site to form an imine, oxime, hydrazone, hydrazide- hyd3?azone, semicarbazone, thiosemicarbazone, hemiacetal or thiohemiacetal linkage between the first nucleotide sequence and the second nucleotide sequence. Certain of these linkages can be reduced to amine, hydroxylamine, hydrazine, hydrazide, semicarbazide or thiosemicarbazide linkages. In a further embodiment of the method, the first bond precursor is attached to a 2'-position of the first nucleotide and the second bond precursor is attached to a 2'-position of the second nucleotide. Preferred linkages for this embodiment include: -N=CH-, -N(R)-, -N(R) -CH 2 -N(R) -, -0-N=CH-, -O-N(R)-, -N(R)-N(R)-, -N(R)-N=CH-, -HC=N-N=CH-, -C (O) -N (R) -N=CH- , -C (0) N (R) - , -C (0) -N (R) -N (R) - , -N (R) -C (0) -N (R) -N (R) - , -N (R) -C (0) -N (R) -N (R) =CH- , -N (R) -C (S) -N (R) -N (R) - , -N (R) -C (S ) -N (R) -N (R) =CH- , -CH (OH) -0-CH 2 - , -CH (OH) -S-CH 2 - , -CH 2 -S-CH 2 -C (0) -CH 2 - , -CH 2 -NH-CH 2 -C (0) -CH 2 - or -S-S- ; wherein R is H, alkyl, alkenyl, aralkyl, an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that enhances the pharmacodynamic properties of oligonucleotides or a group that enhances the pharmacokinetic properties of oligonucleotides. Further in accordance with this invention there are provided methods for cross-linking a single sequence-specific oligonucleotide strand. These methods include selecting first and second nucleotide sequences in the oligonucleotide, incorporating an abasic nucleotide within the first nucleotide sequence, attaching a bond precursor to one of the nucleotides of the second sequence, and forming a covalent cross-linkage between the abasic site and the bond precursor. In one embodiment of this method, the bond precursor is attached to a sugar moiety of the nucleotide of the second sequence, preferably at the 2'-position. In preferred embodiments, the abasic site includes an aldehydic functional group and the bond precursor includes a functional group capable of forming an oxime, imine, hydrazone, hydrazide-hydrazone, semicarbazone, thiosemicarbazone, hemiacetal or thiohemiacetal linkage with the aldehydic functional group. The second nucleotide sequence preferably is selected to be complementary to and specifically hybridizable with the first nucleotide sequence. Further methods for cross-linking a single, sequence- specific oligonucleotide include selecting a first nucleotide sequence and a second nucleotide sequence in the oligonucleo¬ tide. A first bond precursor is attached to a sugar moiety of a nucleotide of the first nucleotide sequence and a second bond precursor is attached to a sugar moiety of a nucleotide of the second nucleotide sequence. A covalent cross-linkage is formed between the first and the second precursors. In preferred embodiments, the cross-linkage is an imine, amine, aminoalkyl- amine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide-hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal, thiohemiacetal, α-keto-alkylthioalkyl or α-keto- alkylaminoalkyl cross-linkage. In other preferred embodiments the second nucleotide sequence is complementary to and hybri¬ dizable with the first nucleotide sequence. Further in accordance with this invention there are provided methods for cross-linking first and second strands of oligonucleotides, comprising the steps of selecting a first nucleotide sequence in a first oligonucleotide strand and selecting a second nucleotide sequence in a second oligonucleotide strand. The methods further include incorporating an abasic nucleotide within the first nucleotide sequence, attaching a bond precursor to a nucleotide of the second sequence, and forming a covalent cross-linkage between the abasic site and the bond precursor. In preferred embodiments, the second nucleotide sequence is complementary to and hybridizable with the first nucleotide sequence. Further, in accordance with this invention there are provided methods for cross-linking first and second strands of oligonucleotides comprising the steps of selecting a first nucleotide sequence in a first oligonucleotide strand, selecting a second nucleotide sequence in a second oligonucleotide strand, attaching a first bond precursor to a sugar moiety of a nucleotide of the first sequence, locating a second covalent precursor on a sugar moiety of a nucleotide of the second sequence, and forming a covalent cross-linkage between the first and the second bond precursors. In preferred embodiments, the second nucleotide sequence is complementary to and hybridizable with the first nucleotide sequence. DETAILED DESCRIPTION OF THE INVENTION In accordance with the objects of this invention novel, covalently cross-linked oligonucleotide strands are dis¬ closed. Preferably such strands are "duplexed" or "complemen- tary" along at least a portion of their length. In the context of this invention the terminology "duplex strands" or "complementary strands" or like terminology refers in a first instance to two separate strands wherein at least one nucleotide or nucleotide sequence on one of the strands is complementary to and specifically hybridizable with an opposing nucleotide or nucleotide sequence on the other strand. In a second instance, this terminology refers to two sections or sequence regions of a single strand that are spaced from one another by a distance sufficient for the strand to fold onto itself and permit hybridization of complementary nucleotides in the respective sequence regions. Folded, self-hybridizing, single strands form hairpin loop, stem loop, interior loop or bulge type structures as a result of such hybridization. Further in the context of this invention, the term "oligonucleotide" refers to polynucleotides formed from a plurality of joined nucleotide units. In certain instances, the nucleotides are formed from naturally occurring bases and pentofuranosyl sugars groups and are joined together via native inter-nucleoside phosphodiester linkages. The term "oligonucleotide" thus effectively includes naturally occurring or synthetic species formed from naturally occurring subunits. The term "oligonucleotide" also includes structures formed from modified or non-naturally occurring nucleotide subunits. Modifications can occur on the base portion of a nucleotide, on a sugar portion .of a nucleotide or on the linkage joining one nucleotide to the next. In addition, modifications can be made wherein nucleoside units are joined together with connecting groups that substitute for the inter-nucleoside phosphate linkages. Inter-nucleoside connecting groups, which are to be distinguished from the cross-linkages of the invention, include -0-CH 2 -CH 2 -0- linkages and other novel linkages disclosed in U.S. Patent Application Serial No. 566,836, filed August 13, 1990, -entitled Novel Nucleoside Analogs, and U.S. Patent Application Serial No. 703,619, filed May 21, 1991, entitled Backbone Modified Oligonucleotide Analogs, both assigned to the assignee of this invention. Other modifications can be made to the sugar, to the base, or to the phosphate group of the nucleotide. Exemplary modifications are disclosed in the following U.S. Patent Applications: Serial No. 463,358, filed January 11, 1990, entitled Compositions And Methods For Detecting And Modulating RNA Activity; Serial No. 566,977, filed August 13, 1990, entitled Sugar Modified Oligonucleotides That Detect And Modulate Gene Expression; Serial No. 558,663, filed July 27, 1990, entitled Novel Polyamine Conjugated Oligonucleotides; Serial No. 558,806, filed July 27, 1991, entitled Nuclease Resistant Pyrimidine Modified Oligonucleotides That Detect And Modulate Gene Expression and serial number PCT/US91/00243, filed January 11, 1991, entitled Compositions and Methods For Detecting And Modulating RNA Activity, all assigned to the assignee of this invention. The disclosures of all of the above-noted patent applications are herein incorporated by reference. The term oligonucleotides, as used in connection with this invention, refers to structures including modified portions such as modified sugar moieties, modified base moieties or modified sugar linking moieties. These modified portions function in a manner similar to natural bases, natural sugars and natural phosphodiester linkages. Thus, in " the context of this invention, oligonucleotides may have altered base moieties, altered sugar moieties or altered inter-sugar linkages. Exemplary among these are: phosphorothioate, phosphorodithioate, methyl phosphonate, phosphotriester or phosphoramidate inter-nucleoside linkages used in place of phosphodiester inter-nucleoside linkages; deaza or aza purines and pyrimidines used in place of natural purine and pyrimidine bases; pyrimidine bases having substituent groups at the 5- or 6-positions; purine bases having altered or replacement substituent groups at the 2-, 6- or 8- positions; or sugars having substituent groups at their 2'-position, substitutions for one or more of the hydrogen atoms of the sugar, or carbo- cyclic or acyclic sugars. Oligonucleotides may also comprise other modifications consistent with the spirit of this inven¬ tion. Such oligonucleotides are best described as being functionally interchangeable with yet structurally distinct from natural oligonucleotides. All such oligonucleotides are comprehended by this invention so long as they effectively mimic the function of a desired RNA or DNA strand. Further in the context of this invention, it will be recognized that the terms "cross-linkage, " "cross-link" or "cross-linking" specifically exclude those portions of the oligonucleotide structure that linearly connect individual nucleoside subunits or nucleoside-like, modified subunits, i . e . , those portions that connect the nucleoside units in the sequence that defines the primary structure of the oligo¬ nucleotide. Thus, "cross-linkage, " "cross-link" or "cross- linking" exclude native phosphodiester linkages that connect nucleosides, as well as analogous, non-native inter-nucleoside linkages such as phosphorothioate, phosphorodithioate methyl phosphonate, phosphotriester, phosphoramidate, and -0-CH 2 - CH 2 -0- linkages used in place of phosphodiester inter-nucleo¬ side linkages. The terms "cross-linkage, " "cross-link" or "cross-linking" as used in the context of this invention refer to "additional" linkages created across a single oligonucleotide strand or several oligonucleotide strands to hold the strand or strands in secondary or other, higher- ordered structures. Primary, secondary, and higher-order structures are as defined in standard reference texts such as Nucleic Acids In Chemistry And Biology, edited by G. Michael Blackburn and Michael J. Gait, Oxford University Press, New York, 1991. Cross-linking is employed in accordance with the present invention to fix separate oligonucleotide strands in duplex structures or to fix a single oligonucleotide strand in a hairpin loop, stem loop, interior loop, bulge or other similar higher-order structure. Such fixation is believed to confer nuclease resistance to oligonucleotides and to optimize structure-dependent function. Fixing a strand or strands in a duplex structure also can disrupt the normal function of single-strand nucleic acid-binding proteins by forming nuclease-resistant mimics of the proteins' binding receptors. Fixing a strand or strands in set secondary structures also makes it possible to mimic the RNA secondary structures found in diseased cells, particularly cells infected with viruses and retroviruses. A detailed delineation of such RNA mimicry is disclosed in Application PCT/US91/01822, filed March 19, 1991, entitled Reagents and Methods For Modulating Gene Expression Through RNA Mimicry, assigned to the same assignee as this application. The entire contents of Application PCT/US91/01822 is herein incorporated by reference. The "fixing" of multiple oligonucleotide strands or a single oligonucleotide strand in defined secondary or other higher-order structure is achieved in accordance with this invention by cross-linking the oligonucleotide strands or oligonucleotide. In one preferred embodiment, novel cross- linkages connect a nucleotide or nucleoside pentofuranosyl moiety on one strand with a nucleotide or nucleoside pento¬ furanosyl moiety on another strand. In another preferred embodiment, novel cross-linkages connect a nucleotide or nucleoside pentofuranosyl moiety on a first region of a single strand with a nucleotide or nucleoside pentofuranosyl moiety on a further region of the same strand. It is believed that such "sugar to sugar" cross-linkages were heretofore unknown. Ii a further embodiment of the invention, novel cross-linkages connect an abasic site on one oligonucleotide strand to a further site on another strand. Also, novel cross-linkages can connect an abasic site on a first region of a single strand with another site on another region of the single strand. It is believed that use of an abasic site as the attachment site for a oligonucleotide cross-linkage was also heretofore unknown. In a further embodiment of the invention, novel cross- linkages of the invention connect a terminal sugar on one oligonucleotide strand or a first region of a single strand with a further site on a further strand or to a further region of a single strand. One preferred cross-linkage of the invention connects the 2'-position of a ribose sugar on one oligonucleotide strand (or a first region of a single strand) to the 2'-position of a ribose sugar on another strand (or a further region of a single strand) . This cross-linkage can be considered a 2' -ribose to 2'-ribose cross-linkage. A second preferred cross-linkage connects a 2' -ribose position on one oligonucleotide strand (or a first region of a single strand) to a Cl'-ribose position (an abasic site) on another strand (or a further region of a single strand). This linkage can be considered a 2'-ribose to Cl'- ribose cross-linkage. A third preferred cross-linkage connects a 2'-ribose position on one strand (or a first region of a single strand) to a seco-ribose on the 3' -terminal end of another strand (or a further region of a single strand) . This linkage can be considered a 2' -ribose to seco-ribose linkage. A fourth preferred cross-linkage connects a 2'-ribose position on one strand (or a first region of a single strand) to 2' and 3' hydroxyls of a nucleoside sugar on the 3' -terminal end of another strand (or a further region of a single strand) . This linkage can be considered a 2'-ribose to 2' ,3' -OH-ribose linkage. For 2' -ribose to 2'-ribose cross-linkages, presently preferred are: cross-linkages between the 2'-hydroxyl groups (or other 2' substituent groups) of the nucleotide sugar moieties of a Watson/Crick nucleotide base pair; a cross- linkage between a 2'-hydroxyl group (or other 2' substituent group) of a nucleotide sugar moiety and a 2'-hydroxyl (or other 2' substituent group) of a nucleotide sugar moiety one base removed (in the 5'-direction) of the opposite strand; a cross- linkage between nucleotides one helical loop removed; or cross- linkage between nucleotides that are separated from each other along the strand or strands but that are located proximal or adjacent to each other in the higher-ordered structure. Molecular models and computer modeling indicate that the 2'- hydroxyls of RNA-RNA duplexes are exposed in the minor groove or minor side. Thus, direct covalent cross-linkage of the 2'-hydroxyls with a linker of appropriate length should not disturb the natural conformation of the duplexes. As per the teachings of this invention, RNA-RNA, DNA-DNA or DNA-RNA type duplexes can be covalently cross-linked via a space-spanning group attached to nucleotide units at desired attachment sites. The length of the space-spanning group on each strand or region of a single strand can be between 1 to about 25 atoms. Thus, when two space-spanning groups are cross-linked together, the total length of the space-spanning groups, the cross-linker, and any other connecting atoms should be less than about 50 atoms in length. The space-spanning groups are composed of carbon atoms or of carbon atoms plus one or more heteroatoms such as nitrogen, sulfur or oxygen. It is preferred that the space- spanning group on an individual strand or on a sequence region of a single strand be about 20 atoms or less in length. More preferably, the cross-linking group is from 8 to 13 atoms in length. For 2'-ribose to Cl' -ribose cross-linkages, a cross-linkage is formed between a 2'-position of a nucleotide sugar moiety on one strand (or on a first region of a single strand) and an abasic l'-site on another strand (or on a further region of a single strand) . The cross-linking group preferably is from 8 to 13 atoms in length. For 2' -ribose to seco-ribose cross-linkages, a cross- linkage is formed between a 3'-terminal ribofuranosyl nucleoside of a first strand and a reactive functionality on a space-spanning group attached to the sugar moiety of a nucleotide on another strand (or on a further region of the first strand) . Preferably, such cross-linkage is made through 2' and 3' hydroxyl groups of the 3'-terminal nucleoside. The 2' and 3' hydroxyl groups are first converted to a 2' ,3' -dialdehyde structure with periodate. A cross-linkage is formed upon hybridization with a complementary strand that has a connecting or space-spanning group bearing a functional group capable of reacting with the aldehydic functionality. If a 2' -aminoalkoxy connecting or space-spanning group is provided on the 2'-ribose strand, reaction of the aldehydic functionality of the seco-ribose strand should form a Schiff's base. Reduction of this Schiff's base with sodium cyanoboro- hydride affords a stable cross-linkage. For 2'-ribose to 2',3' -OH-ribose cross-linkages, a cross-linkage is formed between 2' and 3' hydroxyls of a 3'- terminal ribofuranosyl nucleoside of a first strand and an aldehyde functionality on a space-spanning group attached to a nucleotide sugar moiety on another strand (or on a further region of the first strand) . On hybridization of the strands (or strand) , the aldehyde functionality on the space-spanning group reacts with the 2' ,3'-hydroxyls to form an acetal linkage. Oligonucleotides in accordance with this invention preferably comprise from * about 3 to about 100 subunits. It is preferred that such oligonucleotides comprise greater than about 6 subunits, more preferably from about 8 to about 60 subunits. Oligonucleotides having from about 10 to about 30 subunits are still more preferred. It will be recognized that a subunit comprises a base moiety linked to a sugar moiety. A subunit typically is bound to adjacent subunits through inter- nucleoside bonds. As indicated in the above-referenced United States patent applications, oligonucleotides have diagnostic, therapeutic, and prophylactic applications and also can be used as research reagents. For therapeutic use, cross- linked oligonucleotide analogs can be administered to animals, including humans, suffering from a disease state that it is desirous to treat. It is generally preferred to apply a therapeutic agent of the invention internally such as orally, intravenously or intramuscularly with or without pharmacologically acceptable carriers. Other forms of administration, such as transdermal, topical or intralesional administration, may also be useful. Cross-linked oligonucleotides also can be included in suppositories. In certain embodiments, a space-spanning group bearing an active functional group is located on one strand of a pair of duplexed oligonucleotide strands. Preferably, the space- spanning group is attached to a 2'-position of a nucleotide on the strand. The functional group is positioned on the space- spanning group at a point distal from the point at which the space-spanning group connects to the nucleotide. The space- spanning group is connected to the 2'-position via one or more connecting atoms. Preferably, the connecting atoms includes 0, S, NH, CH 2 or CO. The space-spanning group is preferably a linear or straight chain group. In one embodiment of the invention, the space-spanning group comprises a methylene chain from 1 to about 20 carbon atoms in length. Where the connecting atoms are methylene groups, the connecting group and the space- spanning group together form an alkyl chain. In other embodiments, one or more unsaturated sites are located in the space-spanning group, resulting in alkenyl or alkynyl chains. In these embodiments the alkenyl or alkynyl space-spanning groups have from 2 to about 20 carbon atoms. In other embodiments the space-spanning group further includes branched chains and substituent groups that extend from a backbone or primary straight chain. Branched chains can be selected from branched alkyl, branched alkenyl or branched alkyne space-spanning groups. The branched chains, in addition to the carbon atoms of the main chain, have from 1 to about 30 carbon atoms. Further substituent atoms or substituent groups can also extend from the backbone or from any branched chains. Thus, the space-spanning group can include C 1 -C 20 straight chain alkyl, ^C^ straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne and C 3 -C 50 branched chain substituted alkyne groups. Other space-spanning groups include aryl, aralkyl and heterocyclic groups.- Representative examples of the space-spanning groups include but are not limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl straight chained alkyl groups; 2-methylpropyl, 2-methyl-4-ethylbutyl, 2,4-diethylpropyl, 3- propylbutyl, 2, 8-dibutyldecyl, 6, 6-dimethyloctyl, 6-propyl-6- butyloctyl, 2-methylbutyl, 2-methylpentyl, 3-methylpentyl, 2- ethylhexyl, 3-penten-2-one, 3-methyl-2-butanol, 2-cyanooctyl, 3-methoxy-4-heptanal, 3-nitrobutyl, 4-isopropoxydodecyl, 4- azido-2-nitrodecyl, 5-mercaptononyl, 4-amino-1-pentenyl branched or substituted groups; allyl, crotyl, propargyl, 2- pentenyl unsaturated groups; 4-methylenebenzyl, 1,4-naphthyl, 2,7-anthracyl and 2, 6-phenanthryl aryl or aralkyl groups. Other space-spanning groups include polyamine, polyamide, polyester, polyethylene glycol and polyether, (polyalkoxyalkyl) groups. Polyamines include compounds of the structure [amine functionality- (linker) n . Normally the linker is a methylene chain. The amine functionalities can be primary amines, hydrazines, semicarbazides, thiosemicarbazides or similar nitrogenous species. The number of individual units of the polyamine (n) is selected in conjunction with the number of linker atoms (m) such that the total number of atoms is preferably 20 or less. Thus, if [-HN(CH 2 ) m -] n is selected as the polyamine backbone, n could be from 1 to 10 depending on m. For example, if m is 1, n can range up to 10, and if m is 2, n can range up to 5. If larger nitrogenous species such as hydrazine or semicarbazide are utilized, n and m would be correspondingly smaller to reflect the increased number of atoms contributed by the nitrogenous species. Polyamides, polyesters and polyethylene glycols according to the invention have structures analogous to the above-described polyamines, except that an amide, ester or alcohol functionality is substituted for the nitrogenous species of the polyamine. Polyether groups also have analogous structures, except that one or more ether oxygen atoms are interspersed in the carbon chains. Aryl, aralkyl and heterocyclic space-spanning groups are similar to the above-described alkyl, alkenyl and alkynyl groups, except that appropriate aromatic, mixed alkyl-aromatic or heterocyclic groups are selected. Such space-spanning groups preferably are less than about 20 atoms in length, excluding atoms that are not directly in the space-spanning group chain but are within the structure of the aromatic or heterocyclic ring. Aryl, aralkyl, and heterocyclic space- spanning groups can include up to about 50 atoms. Substituent groups can be present on the above- described alkyl, alkenyl, alkyne, polyamine, polyamide, poly¬ ester, polyethylene glycol, polyether, aryl, aralkyl and heterocyclic space-spanning groups. Substituent groups include but are not limited to halogen, hydroxyl, keto, carboxy, nitrates, nitrites, nitro, nitroso, nitrile, trifluoromethyl, O-alkyl, S-alkyl, NH-alkyl, amino, azido, sulfoxide, sulfone, sulfide, silyl, intercalators, conjugates, polyamines, polyamides, polyethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligonucleotides and groups that enhance the pharmacokinetic properties of oligonucleotides. Typical intercalators and conjugates include cholesterols, phospholipids, biotin, phenanthroline, phenazine, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. Halogens include fluorine, chlorine, bromine and iodine. Groups that enhance pharmaco¬ dynamic properties, in the context of this invention, include groups that improve oligonucleotide uptake, enhance oligonucleotide resistance to degradation, and/or strengthen sequence-specific hybridization with RNA. Groups that enhance pharmacokinetic properties, in the context of this invention, include groups that improve oligdnucleotide uptake, distribution, metabolism or excretion. Nucleotides incorporating a connecting atom, a space- spanning group and a functional group on the end of the space- spanning group are generally synthesized as per the methods and syntheses disclosed in United States Patent Application Serial Nos. 463,358, 566,977 and PCT/US91/00243. To introduce amine- functionalized space-spanning groups on a nucleotide within desired oligonucleotide sequences, 5' -dimethoxytrityl-2' -O, 2' - S or 2' -NH- (space-spanning group-N-phthalimido) nucleoside phosphoramidites are synthesized. The N-phthalimido amine protecting group is removed with concentrated NH 4 OH. N- phthalimido compounds thus provide an amine-functionalized space-spanning group attached to the 2' -position of nucleotide components of an oligonucleotide. The following compounds for forming compounds having amine-functionalized space-spanning groups are commercially available from Aldrich Chemical Co., Inc., Milwaukee, WI: N- (2-bromoethyl)phthalimide, N- (3-bromopropyl)phthalimide and N- (4-bromobutyl)phthalimide. Otherphthalimide-protected amine compounds can be conveniently synthesized from appropriate alkyl, aralkyl or aryl halides and phthalimide. Representative compounds include N- (7-bromoheptyl)phthalimide; N- (8- bromooctyl)phthalimide; N- (9-bromononyl)phthalimide,- N- (10- bromododecyDphthalimide; N- (11-bromoundecyl)phthalimide; N- (12-bromodocecyl)phthalimide; N- (13-bromotridecyl) phthal¬ imide; N- (1 -bromotetradecyl)phthalimide; N- (15-bromopenta- decyl) hthalimide; N- (16-bromohexadecyl) -phthalimide; N- (17- bromoheptadecyl)phthalimide;N- (18-bromooctadecyl)phthalimide; N- (19-bromononadecyl)phthalimide; N- (3-bromo-2-methylpropyl) - phthalimide; N- ( -bromo-2-methyl-3-ethylbutyl)phthalimide; N- (3-bromo-2,2-diethylpropyl)phthalimide; N- (4-bromo-3-propyl- butyl)phthalimide; N- (10-bromo-2,8-dibutyldecyl)phthalimide; N- (8-bromo-6,6-dimethyloctyl)phthalimide;N- (8-bromo-6-propyl-6- butyloctyl)phthalimide; N- (4-bromo-2-methylbutyl)phthalimide; N- (5-bromo-2-methylpentyl)phthalimide; N- (5-bromo-3-methyl¬ pentyl)phthalimide; N- (6-bromo-2-ethylhexyl)phthalimide; N-(5- bromo-3-penten-2-one)phthalimide; N- (4-bromo-3-methyl-2-buta- nol) phthalimide; N- (8-bromo-3-amino-4-chloro-2-cyano- octyl)phthalimide; N- (7-bromo-3-methoxy-4-heptanal)phthal¬ imide; N- (4-bromo-2-iodo-3-nitrobutyl)phthalimide; N- (12-bromo- 4-isopropoxydodecyl)phthalimide; N- (10-bromo-4-azido-2-nitro- decyl)phthalimide; N- (9-bromo-5-mercaptononyl)phthal- imide; N- (5-bromo-4-aminopentenyl)phthalimide; N- (5-bromo-penten-2- yl)phthalimide; N- (3-bromoallyl) phthalimide; N- (4- bromocrotyl)phthalimide; N- (3-bromopropargyl)phthalimide; N- (1- bromonaphth-4-yl)phthalimide; N- (2-bromoanthrac-7-yl) - phthalimide; and N- (2-bromophenanthr-6-yl)phthalimide. Such halide compounds are then reacted with an appropriate 2' - oxygen, 2'-sulfur or 2'-amine nucleoside. In addition to amines (-NH 2 ) , further preferred reactive moieties suitable for the functional groups of the invention include hydrazines (-NH-NH-) , hydroxylamines (-NH-0H) , semicarbazides (-NH-C(O) -NH-NH 2 ) , thiosemicarbazides (-NH-C(S) -NH-NH 2 ) , hydrazones (-N=NH), hydrazides (-C(O)-NH- NH 2 ) , alcohols (-OH), thiols (-SH), and aldehydes (-CH=0) . To introduce a nucleotide having a hydrazine-function- alized space-spanning group at its 2'-position into desired oligonucleotide sequences, 5' -dimethoxytrityl-2' -O-, -2'-S- or -2' -NH- (space-spanning group-N-benzylcarbazide) nucleoside phosphoramidites are synthesized. Once an oligonucleotide incorporating these nucleotides is synthesized, the hydrazine functionality is generated by reduction of the carbazide with palladium on charcoal. To introduce a nucleotide having a hydroxylamine- functionalized space-spanning group at its 2'-position within desired oligonucleotide sequences, 5' -dimethoxytrityl-2' -0-, -2' -S-or-2'-NH- (space-spanninggroup-0-phthalimide)nucleoside phosphoramidites are synthesized. Once an oligonucleotide incorporating these nucleotides is synthesized, the hydroxylamine functionality is generated by treatment of the oligonucleotide with methylhydrazine. Semicarbazide and thiosemicarbazide functionalities on space-spanning groups can be introduced directly without protective groups. 5' -Dimeth- oxytrityl-2' -O-, 2' -S- or2' -NH- (alkylsemicarbazide) -nucleoside phosphoramidites are synthesized and incorporated into desired oligonucleotides to provide a semicarbazide functionalized space-spanning group attached to the 2'-position of a component nucleotide of an oligonucleotide. Hydrazide functionalities are formed on space-spanning groups -via reaction of hydrazine with an nucleotide bearing a 2' -O-alkylester. Alcohol functionalities can be formed on space-spanning groups via Ω-bromo alcohols. The alcohol hydroxyl group is protected with a tetrahydropyran (THP) blocking group. The THP- protected compound is then reacted with an activated nucleoside to attach the THP-protected compound at the 2' -position of the nucleoside. After oligonucleotide synthesis, the THP blocking group is removed to expose the alcoholic functionality. Thiol functionalities can be directly formed via ring opening of a 2,2' -anhydro pyrimidine nucleoside using α.,Ω-dithiol compounds. Alternatively, the thiol functionality of space-spanning compounds can be protected with S-trityl protecting groups. After oligonucleotide synthesis, the S-trityl protecting groups are removed with silver nitrate. Aldehydes used as active functional groups in the formation of cross-linkages can be "masked" as protected aldehydes or aldehyde precursors during initial oligonucleotide synthesis. The aldehyde is generated prior to cross-linking from the protected aldehyde or aldehyde precursor and is utilized as one of the reactants for the formation of a covalent cross-linkage. Representative protected aldehydes are C-formyl, o-methylaminobenzenethio, aryl substituted imidazolidino moieties such as di-phenylimidazolidino, dithianes, bis (p-nitrophenoxy) and acetals. Particularly preferred acetals are ' di-aralkyl acetals such as bis (o- nitrobenzyl) acetals that are removed via catalytic hydro¬ genolysis. The diphenylimidazolidino group, which is removed via hydrazine hydrate/sodium cyanoborohydride treatment, is also particularly preferred. Aldehyde precursors include nitriles, alcohols and esters. Nitriles and esters are reduced to their corresponding aldehydes, while alcohols are oxidized to their corresponding aldehydes. Nitriles can be treated with hydrazine, followed by reduction with sodium cyanoborohydride. Esters can be reduced with lithium aluminum hydride. Alcohols can be oxidized under mild oxidation conditions such as Pfitzner-Moffat conditions. See, J. Am. Chem. Soc , 1965, 87, 5661. - Such conditions have been used by Hansske, et al . , Tetrahedron, 1984, 40, 125, to oxidize 2' or 3' hydroxyl groups of various nucleosides using both a chromic acid oxidation reagent as well as a DMS0/Ac 2 0 oxidation reagent. Aldehyde precursors and protected aldehydes can be used both at the nucleoside/nucleotide level and at the oligonucleotide level. Individual nucleotides (or their nucleoside precursors) incorporating an aldehyde precursor or protected aldehyde can be directly incorporated into an oligo¬ nucleotide. Alternately, an aldehyde precursor can be converted to a protected aldehyde, as with C-formyl protected aldehydes, and then directly incorporated into an oligonucleotide. Upon synthesis of the oligonucleotide, the aldehyde is regenerated from the protected aldehyde or generated from the aldehyde precursor and the oligonucleotide strand is cross-linked with a further oligonucleotide strand or with a further region of the same oligonucleotide strand. lie of aldehyde precursors is suggested for certain oligonuc- leotides, such as mimics of pyrimidine tract sequences located upstream from gene splice junctions. One such pyrimidine tract sequence includes the sequence CCC CTC CCC. Since such tracts only contain pyrimidine nucleotides, acidic oxidation conditions used for conversion of alcohols to aldehydes will not result in acidic de-purination or acidic strand cleavage of the oligonucleotide. As will be recognized, hydrazine, hydroxylamine, semicarbazide, thiosemicarbazide, hydrazone, hydrazide, alcohol or thiol functional groups on one space-spanning group can be reacted with an aldehydic group (a -CH=0 group) on a further space-spanning group as, for example, in the above-described embodiment wherein a 2'-ribose to 2'-ribose linkage is formed. These functional groups also can be reacted with an aldehydic group at the Cl' -position of an abasic site to form a 2'-ribose to Cl' -ribose linkage. Alternatively, these functional groups can be reacted with one of the aldehydic groups of a 2' , 3' - dialdehyde 3'-terminal nucleoside to form a 2'-ribose to a seco-ribose linkage, or to form imine (-C=N-). , hydrazone (-C=N-NH-) , oxime (-0-N=CH-) , send.carbazone (NH-C(O) -NH-N=C-) , thiosemicarbazone (NH-C(S) -NH-N=C-) , azine (-HC=N-N=CH-) , hydrazide-hydrazone (-C(O) -NH-N=C-) , hemiacetal (-CH(OH) -0-CH 2 -) or thiohemiacetal (-CH(OH) -S-CH 2 -) cross- linkages. When an aldehyde on a first strand reacts with an alcohol or a thioacetal on another strand or on a further region of the first strand, the resulting hemiacetal or thio¬ hemiacetal theoretically can react with a further alcohol or thiol group. However, such reaction generally is not kinetically (entropically) favorable, as it usually occurs in a water solution or under other conditions in which the concentration of the further alcohol or thiol group is low. In those embodiments of the invention wherein a cross- linkage is formed between a 2'-ribose on a first strand (or a first region of a single strand) and a 2'-ribose on another strand (or a further region of the single strand) , space- spanning groups and reactive functionalities are attached to each of the strands (or regions of a single strand) . The space-spanning groups and reactive functionalities are attached to the 2'-position of each of the strands (or regions of a single strand), as above, utilizing connecting atoms. The strand or strands are then cross-linked by reaction of the reactive functionalities. Accordingly, the reactive function¬ alities can each be considered "bond precursors" or "bond means" since they together form a covalent bond. Depending upon the reactive functionality on each of the strands (or regions of a single strand) , a covalent bond will be formed as an integral part of the cross-linkage. When a thiol group is the active functionality on each of the strands, oxidization results in a disulfide cross-linkage. When an aldehyde is the functional group on one strand (or a first region on a single strand) and an amine is the functional group on the further strand (or further region on a single strand), an imine (-N=CH-, Schiff's base) cross-linkage results. The imine cross-linkage can be reduced to an amine (- NH-CH 2 -.) using a reducing agent such as sodium cyanoborohydride. Reaction of a hydrazine (-NH-NH-) with an aldehyde yields a hydrazone (-HC=N-NH-) cross-linkage, while reaction of a hydroxylamine (HO-N-) with an aldehyde yields an oxime (-0- N=CH-) cross-linkage. Reaction of an aldehyde with a hydrazide (-C(O) -NH-NH 2 ) yields a hydrazide-hydrazone (-C(O) -NH-N=CH-) cross-linkage, reaction of an aldehyde with a semicarbazide (-NH-C(O) -NH-NH 2 ) yields a semicarbazone (-NH-C(0) -NH-N=C-) cross-linkage, and reaction of an aldehyde with a thiosemicarbazide (-NH-C(S) -NH-NH 2 ) yields a thiosemicarbazone (-NH-C(S) -NH-N=C-) cross-linkage. The hydrazone, oxime, hydrazide-hydrazone, semicarbazone and thiosemicarbazone linkages can be reduced to corresponding hydrazine, hydroxylamine, hydrazide-hydrazine, semicarbazide and thiosemicarbazide, respectively, if desired. The active functional groups on the space-spanning moieties can be reacted with both heterobifunctional and homobifunctional groups. As will be recognized, formaldehyde is a homobifunctional group when it is reacted with two amines. Reaction of formaldehyde with amine functional groups that are attached to each of two strands (or regions of a single strand) yields an aminoalkylamine (-NH-CH 2 -NH-) linkage. Hydrazine also can be used as a bifunctional group to join strands that each have a space-spanning group terminated with an aldehyde. The hydrazine adds to a first aldehyde group to form an aldehyde-hydrazone that, in turn, reacts with the second aldehyde to yield an azine (-CH=N-N=CH-) cross-1inkage. Heterobifunctional groups allow the use of one active functionality on one strand (or a region of a single strand) and the use of a different active functionality on another strand (or another region of a single strand) . Thus, one strand could have an amine functionality on an end of its space-spanning group and another strand could have a thiol functionality on the end of its space-spanning group. Space-spanning groups on one of the strands (or region of a - single strand) may not be necessary where heterobifunctional groups or certain of the above-noted active functionalities are employed. An attaching group, for example a 2' -amino or 2' -thio of a 2' -substituted-2' -deoxy- erythro- pentofuranosyl moiety, could be used directly as an active functionality. The space-spanning group and its active functionality from the other strand could react directly with this 2'-positioned active functionality. For example a 2'- deoxy-2' -thio- ery hro-pentofuranosyl sugar couldbe utilized as the sugar moiety of a selected nucleotide on one strand. An omega thiol group on the space-spanning group of a complementary duplex strand can then be coupled to the first 2'-thio group via a disulfide linkage. Other 2' groups suitable for this type of cross-linkage include 2'-amino groups. A 2'-keto group also could be reacted with a suitable hydrazine or other reactive functionality. A variety of heterobifunctional coupling reagents are available from commercial sources including Pierce (Rockford, II). These reagents include l-ethyl-3- (3- dimethylaminopropyl)carbodimide (a water soluble DCC type coupling reagent) , bifunctional imidoesters such as dimethyl adipimidate dihydrochloride, dimethyl pimelimidate dihydrochloride, and dimethyl 3,3'-dithiobispropionimidate dihydrochloride (for coupling amine groups) , and 2-imino- thiolane (for coupling amines thiols) . Coupling reagents also include compounds having N-hydroxysuccinimide moieties that react with amines, compounds having internal disulfide bonds that can be released to expose an active thiol moiety that can be further coupled via a disulfide bond with a further thiol functionality, and compounds having sulfosuccinimidyl groups {e . g. , N-hydroxysulfosuccinimide) that have different reactivity toward amines than N-hydroxysuccinimides. Coupling reagents further include pyridyl-disulfides that exchange with free thiol moieties, active halogen species such as β-carbonyl alkylhalides, e.g. iodo acetamide, maleimide moieties and photoreactive aryl azides such as phenyl azide. Also, thioisocyanates can be used to couple with active functionali ies on space-spanning groups. The various functional groups of the bifunctional cross-linkers are joined together with suitable linking atoms. Representative, commercially available bifunctional compounds include sulfosuccinimidyl 4- (N-maleimidoethyl)cyclohexane-1- carboxylate, N-succinimidyl 3- (2-pyridyldithio)propionate, N- sulfosuccinimidyl (4-iodoacetyl) aminobenzoate, sulfo¬ succinimidyl 4- (p-maleimidophenyl)butyrate, m-maleimido- benzoyl-N-hydroxysulfosuccinimide ester, succinimidyl 4- (N- maleimidomethyl)cyclohexane-l-carboxylate,bismaleimidohexane, disulfosuccinimidyl tartrate, ethylene glycolbis- (succinimidylsuccinate) , dithiojbis(succinimidylpropionate) , disuccinimidyl suberate, N-hydroxysuccinimidyl-4-azidosalicylic acid, N-5-azido-2-nitrobenzoyloxysuccinimide and sulfonsuc- cinimidyl 2- (.rc-azido-o-nitrobenzamido) -ethyl-1,3'- dithiopropionate. Each of these bifunctional groups are reacted with an appropriate active functionality on the space- spanning group. Thus, oligonucleotide strands (or regions of a single strand) bearing the space-spanning groups are cross- linked through the bifunctional group. The 6-bromo-5,5-dimethoxyhexanohydrazide and N- hydroxysuccinimidyl iodoacetate reagents disclosed by Summerton, et al . and Meyer, et al . , respectively, in the references cited above can also be used as heterobifunctional cross-linking reagents. The hydrazine moiety of the Summerton reagent and the succinimidyl moiety of the Meyer reagent can be linked to one strand of duplex strands and the other strand can be linked to the bromoketone or the iodoacetamido portions of these reagents. For instance, the hydrazine functionality of the Summerton reagent would first be reacted with an aldehydic functionality on one strand, the α-haloketal functionality of the reagent would be activated to an α-haloketone via pH adjustment, and the αt-haloketone would then be further reacted with an amine or thiol functionality on the other strand. The active succinimide functionality of the Meyer reagent would be linked to a first amine functionality on a first strand and the resulting iodoacetamidoalkyl functionality would be linked to a further amine or thiol functionality on the other strand. Since both the Summerton and Meyer reagents can be used to join two amine functionalities (two hydrazine functionalities in the case of the Summerton reagent) , they can also be considered homobifunctional linking reagents. Neither the Summerton reagent nor the Meyer reagent are used in accordance with the invention to couple duplex strands via the 7-position of a purine ring. Thus, no charged (i.e., chem¬ ically unstable) species are formed but, rather uncharged, chemically stable cross-linkages of the structures -CH 2 -S-CH 2 - C(0) -CH 2 - and -CH 2 -NH-CH 2 -C(0) -CH 2 -. By terminating a first oligonucleotide strand at its 3' end with a terminal ribofuranosyl nucleoside, cross-linking to a further oligonucleotide strands (or to a further region of a single strand) can be effected via one of two mechanisms. The first mechanism involves generation of a seco ribose by, for example, periodate oxidation of the 2',3' hydroxyl groups of the 3'-terminal ribose. [See, e . g., Lemaitre, Proc Natl . Acad. Sci . USA, 1986, 84 , 648; Chang, Biochem . J. , 1981, 199, 281; and Easterbrook-Smith, Bur. J. Biochem, 1976, 62, 125.] Such oxidation yields a 2',3' di-aldehyde (a seco ribose), which is reacted with a second strand (or a further region of a single strand) that includes a space-spanning group bearing an active amine functionality. Such reaction yields a Schiff's base, which is reduced with, for example, sodium cyano¬ borohydride, to form an amine cross-linker having an amine group directly coupled to the seco ribose of the 3'-terminal nucleoside of the first oligonucleotide strand. The second mechanism involves formation of an acetal cross-linkage from the 2',3'-hydroxyl groups of the terminal ribose. To form the acetal linkage, the hydroxyl groups of the terminal ribose are reacted with an aldehyde group on a space- spanning group on the second strand (or further region of a single strand) . Acetals of this type have been utilized to attach a nitrogen mustard to a terminal ribose, as described by norre, et al . , Nucleotide and Oligonucleotide Derivatives as Enzyme -and Nucleic Acid Targeted Irreversible Inhibitors, Chemical Aspects, G. Weber (Ed.), Advances Press, Oxford, 1986, pp. 277-299. The nitrogen mustard was then further reacted with a complementary sequence of a short oligonucleotide. Significantly, the cross-linkage was formed via the nitrogen mustard, not via the acetal. As noted above, cross-linkages formed via nitrogen mustards generate charged species that are chemically unstable. The present invention employs an acetal, which does not generate a charged species, to effect cross- linking. Taken together, the space-spanning groups, the functional groups, and the connecting atoms comprise a moiety selected from the group consisting of: C 1 - ~ 2 _ straight chain alkylamine, ^C^ straight chain O-alkylamine, C 1 -C 20 straight chain S-alkylamine, ^C ao straight chain NH-alkylamine, C 1 -C 20 straight chain substituted alkylamine, C^C^ straight chain substituted O-alkylamine, C 1 -C 20 straight chain substituted S- alkylamine, ^C^ straight chain substituted NH-alkylamine, C 2 - C 50 branched chain alkylamine, C 2 -C 50 branched chain O- alkylamine, C 2 -C 50 branched chain S-alkylamine, C 2 -C 50 branched chain NH-alkylamine, C 2 -C 50 branched chain substituted alkylamine, C 2 -C 50 branched chain substituted O-alkylamine, C 2 - C 50 branched chain substituted S-alkylamine, C 2 -C 50 branched chain substituted NH-alkylamine, C 2 -C 20 straight chain alkenyl- amine, C 2 -C 20 straight chain O-alkenylamine, C 2 -C 20 straight chain S-alkenylamine, C 2 -C 20 straight chain NH-alkenylamine, C 2 - C 20 straight chain substituted alkenylamine, C 2 -C 20 straight chain substituted O-alkenylamine, C 2 -C 20 straight chain substituted S-alkenylamine, C 2 -C 20 straight chain substituted NH-alkenylamine, C 3 -C 50 branched chain alkenylamine, C 3 -C 50 branched chain O-alkenylamine, C 3 -C 50 branched chain S- alkenylamine, C 3 -C 50 branched chain NH-alkenylamine, C 3 -C 50 branched chain substituted alkenylamine, C 3 -C 50 branched chain substituted O-alkenylamine, C 3 -C 50 branched chain substituted S- alkenylamine, C 3 -C 50 branched chain substituted NH-alkenylamine, C 2 -C 20 straight chain alkynylamine, C 2 -C 20 straight chain 0-alkynylamine, C 2 -C 20 straight chain S-alkynyl- amine, - C 2 -C 20 straight chain NH-alkynylamine, C 2 -C 20 straight chain substituted alkynylamine, C 2 -C 20 straight chain substi¬ tuted O-alkynylamine, C 2 -C 20 straight chain substituted S- alkynylamine, C 2 -C 20 straight chain substituted NH-alkynylamine, C 3 -C 50 branched chain alkynylamine, C 2 -C 50 branched chain O- alkynylamine, C 3 -C 50 branched chain S-alkynylamine, C 3 -C 50 branched chain NH-alkynylamine, C 3 -C 50 branched chain substituted alkynylamine, C 3 -C 50 branched chain substituted O- alkynylamine, C 3 -C 50 branched chain substituted S-alkynylamine, C 3 -C 50 branched chain substituted NH-alkynylamine, ~ ι ~ ~ 2 - straight chain alkylhydrazine, C- L -C^ straight chain O- alkylhydrazine, L - ^ straight chain S-alkylhydrazine, C- . -C 20 straight chain NH-alkylhydrazine, C 1 -C 20 straight chain substituted alkylhydrazine, C -C 20 straight chain substituted O- alkylhydrazine, C^C^ straight chain substituted S- alkylhydrazine, ^C^ straight chain substituted NH- alkylhydrazine, C 2 -C 50 branched chain alkylhydrazine, C 2 -C 50 branched chain 0-alkylhydrazine, C 2 -C 50 branched chain S- alkylhydrazine, C 2 -C 50 branched chain NH-alkylhydrazine, C 2 -C 50f branched chain substituted alkylhydrazine, C 2 -C Ξ0 branched chain substituted O-alkylhydrazine, C 2 -C 50 branched chain substituted S-alkylhydrazine, C 2 -C 50 branched chain substituted NH- alkylhydrazine, C 2 -C 20 straight chain alkenylhydrazine, C 2 -C 20 straight chain O-alkenylhydrazine, C 2 -C 20 straight chain S- alkenylhydrazine, C 2 -C 20 straight chain NH-alkenylhydrazine, C 2 - C 20 straight chain substituted alkenylhydrazine, C 2 -C 20 straight chain substituted O-alkenylhydrazine, C 2 -C 20 straight chain substituted S-alkenylhydrazine, C 2 -C 20 straight chain substituted NH-alkenylhydrazine, C 3 -C 50 branched chain alkenylhydrazine, C 3 -C 50 branched chain O-alkenylhydrazine, C 3 - C 50 branched chain S-alkenylhydrazine, C 3 -C 50 branched chain NH- branched chain substituted branched chain substituted O- branched chain substituted S- branched chain substituted NH- alkenylhydrazine, C 2 -C 20 straight chain alkynylhydrazine, C 2 -C 20 straight chain 0-alkynylhydrazine, C 2 -C 20 straight chain S- alkynylhydrazine, C 2 -C 20 straight chain NH-alkynylhydrazine, C 2 - C 20 straight chain substituted alkynylhydrazine, C 2 -C 20 straight chain substituted O-alkynylhydrazine, C 2 -C 20 straight chain substituted S-alkynylhydrazine, C 2 -C 20 straight chain substituted NH-alkynylhydrazine, C 3 -C 50 branched chain alkynylhydrazine, C 2 -C 50 branched chain O-alkynylhydrazine, C 3 - C 50 branched chain S-alkynylhydrazine, C 3 -C 50 branched chain NH- branched chain substituted branched chain substituted O- branched chain substituted S- branched chain substituted NH- alkynylhydrazine, C 1 -C 20 straight chain alkylhydroxylamine, C x - C 20 straight chain O-alkylhydroxylamine, C -C 20 straight chain S- alkylhydroxylamine, C 1 -C 20 straight chain NH-alkylhydroxylamine, C j i-C-, ; , straight chain substituted alkylhydroxylamine, C^C- JQ straight chain substituted O-alkylhydroxylamine, C 1 -C 20 straight chain substituted S-alkylhydroxylamine, C-^C^ straight chain substituted NH-alkylhydroxylamine, C 2 -C 50 branched chain alkylhydroxylamine, C 2 -C 50 branched chain O-alkylhydroxylamine, C 2 -C 50 branched chain S-alkylhydroxylamine, C 2 -C 50 branched chain NH-alkylhydroxylamine, C 2 -C 50 branched chain substituted alkylhydroxylamine, C 2 -C 50 branched chain substituted 0- alkylhydroxylamine, C 2 -C 50 branched chain substituted S- alkylhydroxylamine, C 2 -C 50 branched chain substituted NH- alkylhydroxylamine, C 2 -C 20 straight chain alkenylhydroxylamine, C 2 -C 20 straight chain O-alkenylhydroxylamine, C 2 -C 20 straight chain S-alkenylhydroxylamine, C 2 -C 20 straight chain NH- alkenylhydroxylamine, C 2 -C 20 straight chain substituted alkenyl- hydroxylamine, C 2 -C 20 straight chain substituted 0- alkenylhydroxylamine, C 2 -C 20 straight chain substituted S- alkenylhydroxylamine, C 2 -C 20 straight chain substituted NH- alkenylhydroxylamine, C 3 -C 50 branched chain alkenyl- hydroxylamine, C 3 -C 50 branched chain O-alkenylhydroxylamine, C 3 - C 50 branched chain S-alkenylhydroxylamine, C 3 -C 50 branched chain NH-alkenylhydroxylamine, C 3 -C 50 branched chain substituted alkenylhydroxylamine, C 3 -C 50 branched chain substituted O- alkenylhydroxylamine, C 3 -C 50 branched chain substituted S- alkenylhydroxylamine, C 3 -C 50 branched chain substituted NH- alkenylhydroxylamine , C 2 -C 20 straight chain alkynylhydroxylamine, C 2 -C 20 straight chain O- alkynylhydroxylamine, C 2 -C 20 straight chain S-alkynyl- hydroxylamine, C 2 -C 20 straight chain NH-alkynylhydroxylamine, C 2 -C 20 straight chain substituted alkynylhydroxylamine, C 2 -C 20 straight chain substituted 0-alkynylhydroxylamine, C 2 -C 20 straight chain substituted S-alkynylhydroxylamine, C 2 -C 20 straight chain substituted NH-alkynylhydroxylamine, C 3 -C 50 branched chain alkynylhydroxylamine, C 2 -C 50 branched chain 0- alkynylhydroxylamine, C 3 -C 50 branched chain S- alkynylhydroxylamine, C 3 -C 50 branched chain NH- alkynylhydroxylamine, C 3 -C 50 branched chain substituted alkynyl- hydroxylamine, C 3 -C 50 branched chain substituted 0- alkynylhydroxylamine, C 3 -C 50 branched chain substituted S- alkynylhydroxylamine, C 3 -C 50 branched chain substituted NH- alkynylhydroxylamine, C 1 -C 20 straight chain alkylsemicarbazide, C ι -C 20 straight chain O-alkylsemicarbazide, straight chain S-alkylsemicarbazide, C.-C 20 straight chain NH-alkyl- semicarbazide, C x -C 20 straight chain substituted alkylsemicarbazide, ~ ι ~ ~ 2. straight chain substituted 0- alkylsemicarbazide, ^C^ straight chain substituted S- alkylsemicarbazide, ^C,,- straight chain substituted NH- alkylsemicarbazide, C 2 -C 50 branched chain alkylsemicarbazide, C 2 -C 50 branched chain O-alkylsemicarbazide, C 2 -C 50 branched chain S-alkylsemicarbazide, C 2 -C 50 branched chain NH- alkylsemicarbazide, C 2 -C 50 branched chain substituted alkylsemicarbazide, C 2 -C 50 branched chain substituted 0- alkylsemicarbazide, C 2 -C 50 branched chain substituted S- alkylsemicarbazide, C 2 -C 50 branched chain substituted NH- alkylsemicarbazide, C 2 -C 20 straight chain alkenylsemicarbazide, C 2 -C 20 straight chain O-alkenylsemicarbazide, C 2 -C 20 straight chain S-alkenylsemicarbazide, C 2 -C 20 straight chain NH- alkenylsemicarbazide, C 2 -C 20 straight chain substituted alkenylsemicarbazide, C 2 -C 20 straight chain substituted O- alkenylsemicarbazide, C 2 -C 20 straight chain substituted S- alkenylsemicarbazide, C 2 -C 20 straight chain substituted NH- alkenylsemicarbaz ide , C 3 -C 50 branched chain alkenylsemicarbazide, C 3 -C 50 branched chain O- alkenylsemicarbazide, C 3 -C 50 branched chain S-alkenyl¬ semicarbazide, C 3 -C 50 branched chain NH-alkenylsemicarbazide, C 3 -C 50 branched chain substituted alkenylsemicarbazide, C 3 -C 50 branched chain substituted O-alkenylsemicarbazide, C 3 -C 50 branched chain substituted S-alkenylsemicarbazide, C 3 -C 50 branched chain substituted NH-alkenylsemicarbazide, C 2 -C 20 straight chain alkynylsemicarbazide, C 2 -C 20 straight chain 0- alkynylsemicarbazide, C 2 -C 20 straight chain S-alkynyl¬ semicarbazide, C 2 -C 20 straight chain NH-alkynylsemicarbazide, C 2 -C 20 straight chain substituted alkynylsemicarbazide, C 2 -C 20 straight chain substituted O-alkynylsemicarbazide, C 2 -C 20 straight chain substituted S-alkynylsemicarbazide, C 2 -C 20 straight chain substituted NH-alkynylsemicarbazide, C 3 -C 50 branched chain alkynylsemicarbazide, C 2 -C 50 branched chain 0- alkynylsemicarbazide, C 3 -C 50 branched chain S- alkynylsemicarbazide, C 3 -C 50 branched chain NH- alkynylsemicarbazide, C 3 -C 50 branched chain substituted alkynylsemicarbazide, C 3 -C 50 branched chain substituted 0- alkynylsemicarbazide, C 3 -C 50 branched chain substituted S- alkynylsemicarbazide, C 3 -C 50 branched chain substituted NH- alkynylsemicarbazide, C 1 -C 20 straight chain alkylthiosemicarbazide, C 1 -C 20 straight chain O-alkyl- thiosemicarbazide, ^C;,, straight chain S-alkylthiosemicarb- azide, ^C^ straight chain NH-alkylthiosemicarbazide, C x -C 20 straight chain substituted alkylthiosemicarbazide, C^C^ straight chain substituted O-alkylthiosemicarbazide, C^ ^ straight chain substituted S-alkylthiosemicarbazide, C- L -C ao straight chain substituted NH-alkylthiosemicarbazide, C 2 -C 50 branched chain alkylthiosemicarbazide, C 2 -C 50 branched chain O- alkylthiosemicarbazide, C 2 -C 50 branched chain S- alkylthiosemicarbazide, C 2 -C 50 branched chain NH-alkyl- thiosemicarbazide, C 2 -C 50 branched chain substituted alkylthio¬ semicarbazide, C 2 -C 50 branched chain substituted O-alkylthio¬ semicarbazide, C 2 -C 50 branched chain substituted S- alkylthiosemicarbazide, C 2 -C 50 branched chain substituted NH- alkylthiosemicarbazide , C 2 -C 20 straight chain alkenylthiosemicarbazide, C 2 -C 20 straight chain 0- alkenylthiosemicarbazide, C 2 -C 20 straight chain S-alkenylthio- semicarbazide, C 2 -C 20 straight chain NH-alkenylthiosemi- carbazide, C 2 -C 20 straight chain substituted alkenylthiosemi¬ carbazide, C 2 -C 20 straight chain substituted 0-alkenylthiosemi¬ carbazide, C 2 -C 20 straight chain substituted S-alkenylthiosemi¬ carbazide, C 2 -C 2Q straight chain substituted NH-alkenyl- thiosemicarbazide, C 3 -C 50 branched chain alkenylthio¬ semicarbazide, C 3 -C 50 branched chain O-alkenylthiosemi¬ carbazide, C 3 -C 50 branched chain S-alkenylthiosemicarbazide, C 3 - C 50 branched chain NH-alkenylthiosemicarbazide, C 3 -C 50 branched chain substituted alkenylthiosemicarbazide, C 3 -C 3o branched chain substituted O-alkenylthiosemicarbazide, C 3 -C 50 branched chain substituted S-alkenylthiosemicarbazide, C 3 -C 50 branched chain substituted NH-alkenylthiosemicarbazide, C 2 -C 20 straight chain alkynylthiosemicarbazide, C 2 -C 20 straight chain O-alkynyl- thiosemicarbazide, C 2 -C 20 straight chain S-alkynylthiosemi- carbazide, C 2 -C 20 straight chain NH-alkynylthiosemi- carbazide, C 2 -C 20 straight chain substituted alkynylthiosemicarbazide, C 2 - C 20 straight chain substitutedO-alkynylthiosemicarbazide, C 2 -C 20 straight chain substituted S-alkynylthiosemicarbazide, C 2 -C 20 straight chain substituted NH-alkynylthiosemicarbazide, C 3 -C 50 branched chain alkynylthiosemicarbazide, C 2 -C 50 branched chain O-alkynylthiosemicarbazide, C 3 -C 50 branched chain S- alkynyl hiosemicarbazide, C 3 -C S0 branched chain NH-alkynylthio¬ semicarbazide, C 3 -C 50 branched chain substituted alkynylthio¬ semicarbazide, C 3 -C S0 branched chain substituted 0-alkynyl- thiosemicarbazide, C 3 -C 50 branched chain substituted S- alkynylthiosemicarbazide, C 3 -C 50 branched chain substituted NH- alkynylthiosemicarbazide, Cx-C^ straight chain alkylhydrazone, c ι _C 2o straight chain O-alkylhydrazone, C- L -C J Q straight chain S- alkylhydrazone, C x -C^ straight chain NH-alkylhydrazone, C-_- C 20 straight chain substituted alkylhydrazone, C x -C 20 straight chain substituted O-alkylhydrazone, C x -C 20 straight chain substituted S-alkylhydrazone, C 1 -C 20 straight chain substituted NH- alkylhydrazone, C 2 -C 50 branched chain alkylhydrazone, C 2 -C 50 branched chain 0-alkylhydrazone, C 2 -C 50 branched chain S- alkylhydrazone, C 2 -C 50 branched chain NH-alkylhydrazone, C 2 -C 50 branched chain substituted alkylhydrazone, C 2 -C 50 branched chain substituted O-alkylhydrazone, C 2 -C 50 branched chain substituted S-alkylhydrazone, C 2 -C 50 branched chain substituted NH- aIkylhydrazone, C 2 -C 20 straight chain alkenylhydrazone, C 2 -C 20 straight chain O-alkenylhydrazone, C 2 -C 20 straight chain S- alkenylhydrazone, C 2 -C 20 straight chain NH-alkenylhydrazone, C 2 - C 20 straight chain substituted alkenylhydrazone, C 2 -C 20 straight chain substituted O-alkenylhydrazone, C 2 -C 20 straight chain substituted S-alkenylhydrazone, C 2 -C 20 straight chain substituted NH-alkenylhydrazone, C 3 -C 50 branched chain alkenylhydrazone, C 3 -C 50 branched chain O-alkenylhydrazone, C 3 - C so branched chain S-alkenylhydrazone, C 3 -C 50 branched chain NH- branched chain substituted branched chain substituted O- branched chain substituted S- branched chain substituted NH- alkenylhydrazone, C 2 -C 20 straight chain alkynylhydrazone, C 2 -C 20 straight chain 0-alkynylhydrazone, C 2 -C 20 straight chain S- alkynylhydrazone, C 2 -C 20 straight chain NH-alkynylhydrazone, C 2 - C 20 straight chain substituted alkynylhydrazone, C 2 -C 20 straight chain substituted O-alkynylhydrazone, C 2 -C 20 straight chain substituted S-alkynylhydrazone, C 2 -C 20 straight chain substituted NH-alkynylhydrazone, C 3 -C 50 branched chain alkynylhydrazone, C 2 -C 50 branched chain O-alkynylhydrazone, C 3 - C 50 branched chain S-alkynylhydrazone, C 3 -C 50 branched chain NH- alkynylhydrazone, C 3 -C 50 branched chain substituted alkynylhydrazone, C 3 -C 50 branched chain substituted O-alkynyl¬ hydrazone, C 3 -C 50 branched chain substituted S-alkynylhydrazone, C 3 -C 50 branched chain substituted NH-alkynylhydrazone, C 1 -C 20 straight chain alkylhydrazide, C 1 -C 20 straight chain O- alkylhydrazide, C 1 -C 20 straight chain S-alkylhydrazide, C -C 20 straight chain NH-alkylhydrazide, -- - ~ 2. straight chain substituted alkylhydrazide, C--C 20 straight chain substituted 0- alkylhydrazide, ~ ι ~ ~ z straight chain substituted S- alkylhydrazide, C- ^ -Cz o straight chain substituted NH- alkylhydrazide, C 2 -C 50 branched chain alkylhydrazide, C 2 -C 50 branched chain O-alkylhydrazide, C 2 -C 50 branched chain S- alkylhydrazide, C 2 -C 50 branched chain NH-alkylhydrazide, C 2 -C 50 branched chain substituted alkylhydrazide, C 2 -C 50 branched chain substituted 0-alkylhydrazide, C 2 -C 50 branched chain substituted S-alkylhydrazide, C 2 -C 50 branched chain substituted NH- alkylhydrazide, C 2 -C 20 straight chain alkenylhydrazide, C 2 -C 20 straight chain 0-alkenylhydrazide, C 2 -C 20 straight chain S- alkenylhydrazide, C 2 -C 20 straight chain NH-alkenylhydrazide, C 2 - C 20 straight chain substituted alkenylhydrazide, C 2 -C 20 straight chain substituted 0-alkenylhydrazide, C 2 -C 20 straight chain substituted S-alkenylhydrazide, C 2 -C 20 straight chain substituted NH-alkenylhydrazide, C 3 -C 50 branched chain alkenylhydrazide, C 3 -C 50 branched chain 0-alkenylhydrazide, C 3 - C 50 branched chain S-alkenylhydrazide, C 3 -C 50 branched chain NH- branched chain substituted branched chain substituted O- branched chain substituted S- branched chain substituted NH- alkenylhydrazide, C 2 -C 20 straight chain alkynylhydrazide, C 2 -C 20 straight chain O-alkynylhydrazide, C 2 -C 20 straight chain S- alkynylhydrazide, C 2 -C 20 straight chain NH-alkynylhydrazide, C 2 - C 20 straight chain substituted alkynylhydrazide, C 2 -C 20 straight chain substituted O-alkynylhydrazide, C 2 -C 20 straight chain substituted S-alkynylhydrazide, C 2 -C 20 straight chain substituted NH-alkynylhydrazide, C 3 -C 50 branched chain alkynylhydrazide, C 2 -C 50 branched chain O-alkynylhydrazide, C 3 - C 50 branched chain S-alkynylhydrazide, C 3 -C 50 branched chain NH- alkynylhydrazide, C 3 -C S0 branched chain substituted alkynylhydrazide, C 3 -C 50 branched chain substituted O-alkynyl¬ hydrazide, C 3 -C 50 branched chain substituted S-alkynylhydrazide, C 3 -C 50 branched chain substituted NH- lkynylhydrazide, ^G^ straight chain alkanol, C 1 -C 20 straight chain O-alkanol, C x -C 20 straight chain S-alkanol, ^C^ straight chain NH-alkanol, C-_- C 20 straight chain substituted alkanol, ^C^ straight chain substituted O-alkanol, C^C^ straight chain substituted S- alkanol, ^C^ straight chain substituted NH-alkanol, C 2 -C 50 branched chain alkanol, C 2 -C 50 branched chain O-alkanol, C 2 -C 3o branched chain S-alkanol, C 2 -C 50 branched chain NH-alkanol, C 2 - C 50 branched chain substituted alkanol, C 2 -C 50 branched chain substituted O-alkanol, C 2 -C 50 branched chain substituted S- alkanol, C 2 -C 50 branched chain substituted NH-alkanol, C 2 -C 20 straight chain alkenol, C 2 -C 20 straight chain O-alkenol, C 2 -C 20 straight chain S-alkenol, C 2 -C 20 straight chain NH-alkenol, C 2 - C 20 straight chain substituted alkenol, C 2 -C 20 straight chain substituted O-alkenol, C 2 -C 20 straight chain substituted S- alkenol, C 2 -C 20 straight chain substituted NH-alkenol, C 3 -C 3o branched chain alkenol, C 3 -C 50 branched chain O-alkenol, C 3 -C 50 branched chain S-alkenol, C 3 -C 50 branched chain NH.- alkenol, C 3 - C 50 branched chain substituted alkenol, C 3 -C 50 branched chain substituted O-alkenol, C 3 -C 50 branched chain substituted S- alkenol, C 3 -C 3o branched chain substituted NH-alkenol, C 2 -C 20 straight chain alkynol, C 2 -C 20 straight chain O-alkynol, C 2 -C 20 straight chain S- alkynol, C 2 -C 20 straight chain NH- alkynol, C 2 - C 20 straight chain substituted alkynol, C 2 -C 20 straight chain substituted O-alkynol, C 2 -C 20 straight chain substituted S- alkynol, C 2 -C 20 straight chain substituted NH-alkynol, C 3 -C 50 branched chain alkynol, C 2 -C 50 branched chain O-alkynol, C 3 -C S0 branched chain S-alkynol, C 3 -C 50 branched chain NH-alkynol, C 3 - C 50 branched chain substituted alkynol, C 3 -C 50 branched chain substituted O-alkynol, C 3 -C 50 branched chain substituted S- alkynol, C 3 -C 50 branched chain substituted NH-alkynol, C- L -C ZO straight chain alkanthiol, C^C^ straight chain O-alkanthiol, C- L -C JO straight chain S-alkanthiol, C- L -C-, 0 straight chain NH- alkanthiol, Ci-C-, 0 straight chain substituted alkanthiol, C x -C 20 straight chain substituted O-alkanthiol, C^ ,,, straight chain substituted S-alkanthiol, ^C^ straight chain substituted NH- alkanthiol, C 2 -C 50 branched chain alkanthiol, C 2 -C 50 branched chain O-alkanthiol, C 2 -C 50 branched chain S-alkanthiol, C 2 -C S0 branched chain NH-alkanthiol, C 2 -C 50 branched chain substituted alkanthiol, C 2 -C 50 branched chain substituted O-alkanthiol, C 2 - C so branched chain substituted S-alkanthiol, C 2 -C 50 branched chain substituted NH-alkanthiol, C 2 -C 20 straight chain alkenthiol, C 2 -C 20 straight chain O-alkenthiol, C 2 -C 20 straight chain S-alkenthiol, C 2 -C 20 straight chain NH- alkenthiol, C 2 -C 20 straight chain substituted alkenthiol, C 2 -C 20 straight chain substituted O-alkenthiol, C 2 -C 20 straight chain substituted S- alkenthiol, C 2 -C 20 straight chain substituted NH- alkenthiol, C 3 - C so branched chain alkenthiol, C 3 -C 50 branched chain O-alken¬ thiol, C 3 -C 50 branched chain S-alkenthiol, C 3 -C 50 branched chain NH-alkenthiol, C 3 -C 50 branched chain substituted alkenthiol, C 3 - C 50 branched chain substituted O-alkenthiol, C 3 -C 50 branched chain substituted S-alkenthiol, C 3 -C 50 branched chain substituted NH-alkenthiol, C 2 -C 20 straight chain alkynthiol, C 2 - C 20 straight chain 0-alkynthiol, C 2 -C 20 straight chain S-alkynth- iol, C 2 -C 20 straight chain NH-alkynthiol, C 2 -C 20 straight chain substituted alkynthiol, C 2 -C 20 straight chain substituted 0- alkynthiol, C 2 -C 20 straight chain substituted S-alkynthiol, C 2 - C 20 straight chain substituted NH-alkynthiol, C 3 -C 50 branched chain alkynthiol, C 2 -C 50 branched chain O-alkynthiol, C 3 -C 50 branched chain S-alkynthiol, C 3 -C Ξ0 branched chain NH- alkynthiol, C 3 -C 50 branched chain substituted alkynthiol, C 3 -C S0 branched chain substituted O-alkynthiol, C 3 -C 50 branched chain substituted S-alkynthiol and C 3 -C 50 branched chain substituted NH-alkynthiol. The present invention also provides oligonucleotide cross-linkers for connecting two oligonucleotide strands or for connecting two separate regions of a single strand. In certain embodiments, the cross-linkers are of a structure: X-i"- I—-*- I ""- I— - ~ Λp wherein X x is covalently connected to the first strand or to a first region of a single strand and X 2 is covalently connected to the second strand or to a further region of a single strand and where: (i) X x and X 2 , independently, are 0, S, NH, CH 2 or CO; L x and L 2 , independently, are C 1 -C 20 straight chain alkyl, C^C^ straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain - substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 2C straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, polyether, aryl, aralkyl or heterocyclic; and Y is an imine, amine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide-hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal, thiohemiacetal, α-keto-alkylthioalkyl or α-keto-alkylaminoalkyl; or (ii) X x and X 2 , independently, are 0 or NH; and L- . -Y-I- 2 together are NH-L 3 -NH or NH-NH-L 3 -NH-NH; and L 3 is C--C 20 straight chain alkyl, C 1 -C 20 straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain branched chain subs-t feE-t-sd-aάicynef polyamine, po yamide, " polyester, polyethylene glycol, polyether, aryl, aralkyl or heterocyclic; or (iii) X τ and X 2 , independently, are 0, S, NH, CH 2 or CO; L- L and L 2 , independently, are C^C^ straight chain alkylamino, C^C^ straight chain substituted alkylamino, C 2 -C 50 branched chain alkylamino, C 2 -C 50 branched chain substituted alkylamino, C 2 -C 20 straight chain alkenylamino, C 2 -C 20 straight chain substituted alkenylamino, C 3 -C 50 branched chain alkenylamino, C 3 -C 50 branched chain substituted alkenylamino, C 2 -C 20 straight chain alkynylamino, C 2 -C 20 straight chain substituted alkynylamino, C 3 -C 50 branched chain alkynylamino, C 3 -C 50 branched chain substituted alkynylamino, C--C 20 straight chain alkylthio, C- L - ^ straight chain substituted alkylthio, C 2 -C 50 branched chain alkylthio, C 2 -C 50; branched chain substituted alkylthio, C 2 -C 20 straight chain alkenylthio, C 2 -C 20 straight chain substituted alkenylthio, C 3 -C 50 branched chain alkenylthio, C 3 -C 50 branched chain substituted alkenylthio, C 2 -C 20 straight chain alkynylthio, C 2 -C 20 straight chain substituted alkynylthio, C 3 -C 50 branched chain alkynylthio or C 3 -C 50 branched chain substituted alkynylthio; and Y is a heterobifunctional or homobifunctional cross-linking reagent; where said substituent of said substituted alkyl, substituted alkenyl and substituted alkyne moieties is an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that enhances the pharmacodynamic properties of oligonucleotides or a group that enhances the pharmacokinetic properties of oligonucleotides. As illustrated in the examples below, the invention further includes methods for fixing a sequence-specific oligonucleotide in a set configuration. These methods include selecting a first site in the oligonucleotide. The -first site is selected to have a first specific sequence of nucleotides. A first bond precursor is attached to a sugar moiety of one of the nucleotides of the first site. The first bond precursor is for forming a covalent bond. The methods include selecting a second site in the oligonucleotide. The second site is selected to have a second specific nucleotide sequence. A second bond precursor is attached to a sugar moiety of a nucleotide of the second site. The second bond precursor also is for forming a covalent bond. The methods further include forming a covalent cross-linkage between the first and the second bond precursors. The covalent cross-linkage is independent of the phosphate inter-nucleoside linkages that define - the primary structure of the oligonucleotide. In certain embodiments, the methods further include attaching the first bond precursor to a sugar moiety of a nucleotide of the first site by reacting a precursor of the nucleotide with a suitable reagent, derivatizing the nucleotide precursor to a protected and activated form, and then synthetically incorpora¬ ting the derivatized nucleotide precursor into the first nucleotide sequence. In still other embodiments, the methods further include attaching the second bond precursor to a sugar moiety of a nucleotide of the second site by reacting a precursor of the nucleotide with a suitable reagent, derivatizing the nucleotide precursor to a protected and activated form, and synthetically incorporating the derivatized precursor into the second nucleotide sequence. The invention further includes methods for the intra- strand cross.-linkage of an oligonucleotide. In certain embodiments, the methods include the steps of selecting a first nucleotide sequence and a second nucleotide sequence in the oligonucleotide, incorporating an abasic nucleotide within the first sequence, attaching a bond precursor to a nucleotide of the second sequence, and forming a covalent cross-linkage between the abasic site and the bond precursor. In other embodiments, the methods include selecting a first nucleotide sequence and a second nucleotide sequence in the oligonucleotide, attaching a first bond precursor to a sugar moiety of a nucleotide of the first specific sequence, attaching a second bond precursor to a sugar moiety of a nucleotide of the second sequence, and forming covalent cross- linkage between the first and the second bond precursors. This covalent cross-linkage is independent of the phosphate inter- nucleotide linkages that define the primary structure of the oligonucleotide. Preferably, the first nucleotide sequence is selected to be complementary to and hybridizable with the second nucleotide sequence. The invention further includes methods for cross- linking first and second oligonucleotide strands including the steps of selecting a first nucleotide sequence in a first oligonucleotide strand, selecting a second nucleotide sequence in a second oligonucleotide strand, incorporating an abasic nucleotide within the first nucleotide sequence, attaching a bond precursor to a nucleotide of the second sequence, and forming a covalent cross-linkage between the abasic site and the bond precursor. These methods can further include selecting the first nucleotide sequence to be complementary to and hybridizable with the second nucleotide sequence, attaching the bond precursor at a 2' -position of a nucleotide of the second sequence, and forming an aldehydic functional group at the abasic site. The bond precursor should be capable of forming an oxime, imine, hydrazone, semicarbazone, thiosemicarbazone, hydrazide-hydrazone, hemiacetal or thiohemiacetal linking group with the abasic site aldehydic functional group. The invention further includes methods for cross- linking first and second oligonucleotide strands including the steps of selecting a first nucleotide sequence in a first oligonucleotide strand, selecting a second nucleotide sequence in a second oligonucleotide strand, attaching a first bond precursor to a sugar moiety of a nucleotide of the first sequence, attaching a bond precursor on a sugar moiety of a nucleotide of the second sequence, and forming a covalent cross-linkage between the first and the second bond precursors. This covalent cross-linkage is independent of the phosphate inter-nucleotide linkages that define oligonucleotide primary structure. The following examples are illustrative of the invention. It is understood that this invention is not limited by these illustrative examples but solely by the claims appended hereto. EXAMPLE 1 Standard Oligonucleotide Synthesis Oligonucleotide syntheses were performed on an Applied Biosystems 380 B or 394 DNA synthesizer following standard phosphoramidite protocols and cycles using reagents supplied by the manufacture. When modified phosphoramidites are used, a longer coupling time (10-15 min) was employed. The oligonucleotides were normally synthesized in either a 10 μmol scale or a 3 x 1 μmol scale in the "Trityl-On" mode. Standard deprotection conditions (30% NH 4 0H, 55°C, 16 hr) were employed. HPLC was performed on a Waters 600E instrument equipped with a model 991 detector. For analytical chromatography, the following reverse phase HPLC conditions were employed: Hamilton PRP-1 column (15 x 2.5 cm) ; solvent A: 50mm TEAA, pH 7.0; solvent B: 45mm TEAA with 80% CH 3 CN; flow rate: 1.5ml/min; gradient: 5% B for the first 5 minutes, linear (1%) increase in B every minute thereafter. For preparative purposes, the following reverse phase HPLC conditions were employed: Waters Delta Pak Waters Delta-Pak C 4 15 μm, 300A, 25x100 mm column equipped with a guard column of the same material; column flow rate: 5ml/min; gradient: 5% B for the first 10 minutes, linear 1% increase for every minute thereafter. Following HPLC purif¬ ication, oligonucleotides are detritylated and further purified by size exclusion using a Sephadex G-25 column. All oligonucleotide sequences are listed in a standard 5' to 3 ' order from left to right. EXAMPLE 2 Preparation Of Activated and Protected Nucleotides Having A Space-spanning Group And Active Functional Group A. Preparation of 5' -Dimethoxytrityl-2' -0- (Function¬ alized Space-spanning Group)Nucleoside Phosphoramidites i. 5' -Dimethoxytrityl-2' -O- (Pentyl-N-phthal- imido) -N6-Benzyladenosine Phosphoramidite 5' -Dimethoxytrityl-2' -0- (pentyl-N-phthalimido) -N6- benzyladenosine phosphoramidite was synthesized as per the procedures of United States Patent Applications US91/00243 and 463,358, herein incorporated by reference, starting from adenosine. Briefly, this procedure treats adenosine with NaH in DMF followed by treatment with N- (5-bromopentyl)phthalimide (Transworld Chemical Co. Inc., Rockville, MD) . Further treatment with (CH 3 ) 3 SiCl, Ph-C(0)-Cl and NH 4 OH yielded N6- benzyl ■ protected 2' -pentyl-N-phthalimido functionalized adenosine. Treatment with DIPA and CH 2 C1 2 added a DMT blocking group at the 5' -position. Finally phosphitylation gave the desired phosphoramidite compound. ii. 5' -Dimethoxytrityl-2 / -O- (2-Methyloctyl-N- phthalimido) -N4-Benzylcytidine Phosphoramidite a. N- (8-bromo-2-methyloctyl)phthalimide 8-Bromo-2-methylaminooctane is treated with phthalic anhydride in toluene in the presence of triethylamine under reflux. The solvent is removed in vacuo. The residue, when triturated with water, acidified with hydrochloric acid and crystallized from alcohol will yield N- (8-bromo-2- methyloctyl)phthalimide. b. Preparation of 5' -Di ethoxytrityl-2' -0- (2-Methyloctyl-N-Phthalimido) -N4-Benzylcytidine Phosphoramidite Cytidine, when treated with NaH and N- (8-Bromo-2- methyloctyl)phthalimide followed by treatment with DIPA and CH 2 C1 2 and phosphitylation utilizing the procedure of Example 2-A-i, will give 5' -dimethoxytrityl-2' -0- (2-methyloctyl-N- phthalimido) -N4-benzylcytidine phosphoramidite. c. 5' -Dimethoxytrityl-2' -0- (Eicosyl-N- Phthalimido) denosine Phosphoramidite N- (20-bromoeicosyl)phthalimide is prepared as per the procedure of Example 2-A-ii-a from l-amino-20-bromoeicosane. Adenosine is treated with NaH in DMF and l-amino-20- bromoeicosane, benzylated, treated with DIPA and CH 2 C1 2 and phosphitylation as per the procedure of Example 2-A-ii will yield the title compound. iii. 5' -Dime hoxytrityl-2' -O- (Eicosyl-N-Phthal- i ido)Uridine Phosphoramidite N- (20-bromoeicosyl)phthalimide is prepared as per the procedure of Example 2-A-ii-a from l-amino-20-bromoeicosane. Uridine is treated as per the procedure of Akiyama, et al., NOTES Bull . Chem. Soc Jpn . , 1990, 63 , 3356, to give 3- (4- methoxyphenylmethyl) -3' , 5' -0- (tetraisopropyldisiloxane-1,3- diyl)uridine. Briefly this treatment first blocks the 3' and 5' sugar hydroxyls of uridine followed by blocking the N3 imide group of the pyrimidine heterocycle with a p-methoxybenzyl group. Treatment of the blocked uridine with Ag 2 0 and N- (20- bromoeicosyl)phthalimide will yield a 2'-alkylated blocked intermediate compound. The tetraisopropyldisiloxane blocking group is removed by taking the uridine intermediate up in CH 3 CN and treating with 60% HF. The p-methoxyphenylmethyl blocking group is removed by treatment with A1C1 3 in anisole under a N 2 atmosphere followed by Hcl . Both of these procedures are conducted as per the above procedure of Akiyama et al . Further treatment as per the procedure of Example 2-A-ii with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5'-position followed by phosphitylation will yield the title compound. iv. 5' -Dimethoxytrityl-2' -O- (2-Amylenyl-N- phthalimido) -N2-Isobutyrylguanosine Phosphoramidite N- (5-bromo-2-amylenyl)phthalimide is prepared as per the procedure of Example 2-A-ii-a from l~amino-5-bromoamyl-2- ene. 3' , 5' -O- (Tetraisopropyldisiloxane-1, 3-diyl) -2-chloro-6- (2,6-dichlorophenoxy)purine riboside is prepared as described by Sproat, Nucleic Acid Res . , 1990, 18, 41. Treatment of the latter compound with the first followed by deblocking and enzymatic deaminization with adenosine deaminase utilizing the procedure of Sproat, Nucleic Acids Research, 1991, 19, 733, will yield the desired 2'-alkylated guanosine intermediate. Further treatment of this alkylated guanosine intermediate as per the procedure of Example 2-A-i with (CH 3 ) 3 SiCl, isobutyryl chloride and NH 4 OH yields N2-isobutyryl protected 2'-amylenyl- N-phthalimido functionalized guanosine. Treatment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position followed by phosphitylation will give the desired phos¬ phoramidite compound. v. 5' -Dimethoxytrityl-2' -O- (Ethyl-N-Phthal- imido)Thymidine Phosphoramidite Thymidine is blocked and treated with Ag 2 0 and N- (2- bromoethyl)phthalimide (Aldrich Chemical Co., Inc., Milwaukee, WI) as per the procedure of Example 2-A-iii followed by further treatment as per the procedure of Example 2-A-i with DΪPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position and finally phosphitylation will yield the title compound. vi. Preparation of Other 5' -Dimethoxytrityl-2' - 0- (Phthalimido Blocked Amine Functionalized Space-spanning Group) -Nucleoside Phosphoramidites a. Preparation of N- (Ω-bromoalkyl, Ω- bromoalkenyl and Ω-bromoalkynyl)phthalimides In the manner of Example 2-A-ii-a the following Ω- bromo phthalimide blocked amine compounds, useable as amine functionalized space-spanning groups, can be prepared: N- (7-bromoheptyl)phthalimide;N- (8-bromooctyl)phthal- imide; N- (9-bromononyl)phthalimide; N- (10-bromododecyl) - phthalimide; N- (11-bromoundecyl) phthalimide; N-(12- bromodocecyl)phthalimide; N- (13-bromotridecyl)phthalimide; N- (14-bromotetradecyl)phthalimide; N- (15-bromopentadecyl) - phthalimide; N- (16-bromohexadecyl)phthalimide; N- (17- bromoheptadecyl)phthalimide;N- (18-bromooctadecyl)phthalimide; N- (19-bromononadecyl)phthalimide; N- (3-bromo-2-methyl- propyl ) phthalimide ; N- (4 -bromo-2 -methyl-3 -ethyl - butyl)phthalimide; N- (3-bromo-2,2-diethylpropyl) hthalimide; N- (4-bromo-3-propylbutyl)phthalimide; N- (10-bromo-2, 8-dibutyl- decyl)phthalimide; N- (8-bromo-6,6-dimethyloctyl)phthalimide; N- (8-bromo-6-propyl-6-butyloctyl)phthalimide; N- (4-bromo-2- methylbutyl)phthalimide; N- (5-bromo-2-methylpentyl)phthalimide; N- (5-bromo-3-methylpentyl)phthalimide; N- (6-bromo-2-ethyl- hexyl)phthalimide; N- (5-bromo-3-penten-2-one)phthalimide; N- (4- bromo-3-methyl-2-butanol)phthalimide; N- (8-bromo-3-amino-2- cyanooctyl ) phthalimide ; N- ( 7 -bromo - 3 -methoxy-4 - heptanal)phthalimide; N- (4-bromo-2-iodo-3-nitrobutyl) - phthalimide; N- (12-bromo-4-isopropoxydodecyl)phthalimide; N- (10-bromo-4-azido-2-nitrodecyl)phthalimide; N- (9-bromo-5- mercaptononyl ) phthalimide ; N- ( 5 -bromo -4 - aminopentenyl)phthalimide;N- (5-bromo-penten-2-yl)phthalimide; N- (3-bromoallyl)phthalimide; N- (4-bromocrotyl)phthalimide; N- (3 -bromopropargyl) phthalimide; N- (l-bromonaphth-4- yl)phthalimide; N- (2-bromoanthrac-7-yl)phthalimide; and N-(2- bromophenanthr-6-yl)phthalimide. b. Preparation of 5' -Dimethoxytrityl-2' -O- (N-Phthalimide Functionalized Space-spanning Group)Nucleoside Phosphoramidites In the manner of Examples 2-A-i, 2-A-ii-b, 2-A-iii, 2-A-iv and 2-A-v, the following 5' -dimethoxytrityl-2' -0- (space- spanning group-N-phthalimide)nucleoside phosphoramidite can be prepared: 5' -dimethoxytrityl-2' -0- (dodecyl-N-phthalimido) -N4- benzylcytidine phosphoramidite; 5' -dimethoxytrityl-2' -0- (tetra- decyl-N-phthalimido) -N6-benzyladenosine phosphoramidite; 5'- dimethoxytrityl-2' -0- (2-methylpropyl-N-phthalimido)uridine phosphoramidite; 5' -dimethoxytrityl-2' -0- (2,8-dibutyldecyl-N- phthalimido) -N2-isobutyrylguanosine phosphoramidite;. 5'- dimethoxytrityl-2' -O- (3-methylpentyl-N-phthalimido)thymidine phosphoramidite; 5' -dimethoxytrityl-2' -0- (2-cyanooctyl-N- phthalimido) -N4-benzylcytidine phosphoramidite; 5' -dimethoxy¬ trityl-2' -0- (3-methoxy-4-heptanal-N-phthalimido) uridine phosphoramidite; 5' -dimethoxytrityl-2' -0- (3-nitrobutyl-N- phthalimido) -N6-adenosine phosphoramidite; 5' -dimethoxytrityl- 2'-0- (propargyl-N-phthalimido) -N2-isobutyrylguanosine phosphor¬ amidite; and 5'-dimethoxytrityl-2' -0- (3-anthrac-7-yl-N-phthal¬ imido)thymidine phosphoramidite. B. Preparation of 5'-Dimethoxytrityl-2' -S-(Amine Functionalized Space-spanning Group) -2'-Deoxy-Nucleoside Phosphoramidites i. Preparation of N- (1-Bromo-8-dodecyl)Phthal¬ imide l-Aminododecyl-12-ol is treated with N-ethoxycarbon- ylphthalimide utilizing the reaction conditions of McArthur, et. al . , Synth . Commun . , 1983, 13 , 311, to yield N- (dodecyl-12- ol)phthalimide which in turn when treated with phosphorous tribromide and pyridine utilizing the reaction conditions of Hall, et al . , Synthetic Procedures in Nucleic Acid Chemistry, Zorbach and Tipson, Editors, Volume 1, John Wiley & Sons, 1968 will yield N- (12-bromododecyl)phthalimide. ii. 5' -Dime hoxytrityl-2'-S- (Dodec-12-N-Phthal- i ido) -2 ' -Deox uridine Phosphoramidite 2' -Deoxy-2-thiouridine is prepared as per the procedure of Divakar, J. Chem. Soc. Perkin Trans . , 1990, 1, 969. 2' -Deoxy-2-thiouridine when treated with NaH in DMF followed by treatment with N- (12-bromododecyl)phthalimide will yield 2 ' -S- (dodecyl-N-phthalimido) functionalized uridine. Treatment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position followed by phosphitylation will give the desired phosphoramidite compound. C. Preparation of 5' -Dimethoxytrityl-2' -NH- (Alkyl-N- Phthalimido) -2 ' -Deoxy-Nucleoside Phosphoramidites i. N- (Butyl-4-al)Phthalimide (an Ω-aldehydic terminating α-N-Phthalimide functionalized space-spanning group) 4-Aminobutyraldehyde diethyi acetal (Aldrich Chemical Co., Inc., Milwaukee, WI) when treated with phthalic anhydride in toluene in the presence of triethylamine as per the procedure of Example 2-A-ii-a will give an N-phthalimide blocked amine group at the 1-position of the butyl group and an diethyi acetal blocked aldehyde group at the 4-position. The diethyi acetal blocking group is then removed by acid catalyzed hydrolysis to give N- (butyl-4-al)phthalimide. ii. 5' -Dimethoxytrityl-2' -NH- (Butyl-N-Phthal- imido) -2'-Deoxy-N6-Benzyladenosine Phosphoramidite 2' -Amino-N6-benzyl-2'-deoxyadenosine, prepare as per the procedure of G. Burke, et. al . , J. Carbohydrates, Nucleosideε, Nucleotides, 1988, 7, 63, and N- (butyl-4- al)phthalimide are stirred in dry CH 2 C1 2 . The solvent is removed and the residue taken up in NaOAc buffer (pH 5.02) and treated with NaCNBH 3 to reduce the intermediate imine to the desired amine linking functionality. Further treatment as per the procedure of Example 2-A-i with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5'-position followed by phosphitylation will yield the title compound. D. Preparation of 5'-Dimethoxytrityl-2' - (Alkyl-N- Phthalimido) -2'-Deoxy-Nucleoside Phosphoramidites Introduction of a 2' directly alkylated nucleotide (i.e. a methylene linking group joining a space-spanning group to the 2'-position of a nucleotide sugar moiety) into an oligonucleotide is accomplished by free radical alkylation of the corresponding nucleoside followed by conversion to the appropriate 5' -dimethoxytrityl phosphoramidite nucleotides. i. 5'-Dimethoxytrityl-2 ' - (Allyl-N-Phthalimido) - 2 '-Deoxy-N6-Benzyladenosine Phosphoramidite 2' -O- (Phenoxythioxomethyl) -2 ' -deoxyadenosine will be treatedwithN- (5-bromopenten-2-yl)phthalimide (fromExample 2- A-vi) and tributyltin hydride utilizing conditions analogous to those described in Flandor, et al . , Tetrahedron Letters, 1990, 31 , 597, to effect a free radical alkylation at the 2' -position of the nucleoside. The resulting alkylated compound is then further treated with (CH 3 ) 3 SiCl, Ph-C(0)-Cl and NH 4 OH to give the N6-benzyl protected 2' - [N- (penten-2-yl)phthalimido] functionalized adenosine. This is then followed by treatment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5'- position which in turn is followed by phosphitylation, all as per the procedure of Example 2-A-i, to give the desired phosphoramidite compound. ii. 5'-Dimethoxytrityl-2'- (Allyl-N-Phthalimido)- 2'-Deoxyuridine Phosphoramidite 2' -0- (Phenoxythioxomethyl) -2' -deoxyuridine will be treated with N- (5-bro openten-2-yl)phthalimide (from Example 2- A-vi) and tributyltin hydride utilizing conditions analogous to those described in Flandor, et al . , Tetrahedron Letters, 1990, 31 , 597 to effect a free radical alkylation at the 2' -position of the nucleoside. The resulting alkylated compound is then further treated with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position which in turn is followed by phosphit¬ ylation-, all as per the procedure of Example 2-A-iii, to give the desired phosphoramidite compound. E. Preparation of 5' -Dimethoxytrityl-2' -O- (Hydrazine FunctionalizedSpace-spanningGroup)NucleosidePhosphoramidites i. 8-Bromooctylbenzylcarbazide (an α-bromo carbazide protected Ω-hydrazine functionalized space-spanning group) 8-Bromooctanol is tosylated with tosyl chloride in pyridine. The solvent is removed and the 8-bromooctanol O- tosylate is treated with benzylcarbazide and activated molecular sieves in anhydrous dimethylacetamide overnight at 110°C. The solvent is removed and the residue purified by silica gel chromatography to yield bromooct-8-ylbenzylcar- bazide. ii. 5' -Dimethoxytrityl -2 ' -0- (Oct-8-ylbenzylcarb- azide) ridine Phosphoramidite Uridine will be treated with 8-bromooctylbenzyl- carbazide utilizing the method of Example 2-A-iii to give the title compound. iii. 5'-Dimethoxytrityl-2" -O- (Oct-8-ylbenzyl- carbazide) -N4-Benzylcytidine Phosphoramidite Cytidine will be treated with 8-bromooctyl- benzylcarbazide utilizing the method of Example 2-A-ii-b to give the title compound. ' iv. 5' -Dimethoxytrityl-2' -O- (Oct-8-ylbenzylcarb- azide) -N2-Isobutyrylguanosine Phosphoramidite Guanosine will be treated with 8-bromooctyl- benzylcarbazide utilizing the method of Example 2-A-iv to give the title compound. v. 5' -Dimethoxytrityl-2'-0- (Oct-8-ylbenzylcarb- azide) -N6-Benzyladenosine Phosphoramidite Adenosine will be treated with 8-bromooctyl- benzylcarbazide utilizing the method of Example 2-A-i to give the title compound. F. Preparation of 5'-Dimethoxytrityl-2' -O- (Hydroxyl¬ amine-Functionalized Space-spanning Group)Nucleoside Phosphor¬ amidites i. 0- (8-Bromooctanol)phthalimide (an α-bromo 0- phthalimide protected Ω-hydroxylamine functionalized space- spanning group) 1,8-0ctanediol is treated with one equivalent of dihydropyrane in the presence of acid to give the 8- (tetrahydropyran-2-yl)octanol. 8- (Tetrahydropyran-2- yDoctanol, N-hydroxyphthalimide and triphenylphosphine in DMF are treated at 0°C with diisopropylazodicarboxylate utilizing Mitsunobu reaction conditions to give 0- [8- (tetrahydropyran-2- yl)octanol)phthalimide. Acid treatment of 0- [8- (tetrahydro- pyran-2-yl)octanol]phthalimide will yield 0- (octanol)phthal- imide which in turn when treated with phosphorous tribromide and pyridine utilizing the reaction conditions of Hall, et al . , Synthetic Procedures in Nucleic Acid Chemistry, Zorbach and Tipson, Editors, Volume 1, John Wiley & Sons, 1968 will yield 0- (8-bromooctanol) hthalimide. ii. 5'-Dimethoxytrityl-2'-0- (Octan-8-ol-O- Phthalimido)-N4-Benzylcytidine Phosphoramidite Cytidine is treated with NaH in DMF followed by treatment with 0- (8-bromooctanol)phthalimide from Example 2-F- i. Further treatment with (CH 3 ) 3 SiCl, Ph-C(0)-Cl and NH 4 0H will yieldN4-benzyl protected2' -octyl-O-phthalimido functionalized cytidine. Treatment with DIPA and CH 2 C1 2 will add a DMT blocking group at the 5' -position. Finally phosphitylation as per the procedure of Example 2-A-ii will give the desired phosphoramidite compound. iii. 5'-Dimethoxytrityl-2 # -O- (Octan-8-ol-O- Phthalimide)uridine Phosphoramidite Uridine is blocked and then treated with Ag 2 0 and 0- (8-bromooctanol)phthalimide from Example 2-F-i. Treatment with DIPA and CH 2 C1 2 will add a DMT blocking group at the 5'- position. Finally phosphitylation as per the procedure of Example 2-A-iii will give the desired phosphoramidite compound. G. Preparation of 5'-Dimethoxytrityl-2' -O- (Semicar¬ bazide Functionalized Space-spanning Group)Nucleoside Phosphor¬ amidites i. 5 7 -Dimethoxytrityl-2' -O- (pent-5-ylsemicar- bazide)uridine Phosphoramidite Uridine is blocked and then treated with Ag 2 0 and N- (8-bromopenyl) semicarbazide utilizing the method of Example 2- A-iii to give the title compound. ii. 5' -Dimethoxytrityl-2' -O- (pent-5-ylsemicar- bazide) -N6-Benzyladenosine Phosphoramidite Adenosine will be treated with N- (8-bromopenyl) - semicarbazide utilizing the method of Example 2-A-i to give the title compound. H. Preparation of 5' -Dimethoxytrityl-2' -O- (Hydrazide FunctionalizedSpace-spanningGroup)NucleosidePhosphoramidites i. α-Cloroethoxycarbonylethane Chloroacetyl chloride (Air Products, Emmaus, PA) is added drop wise to stirring ethanol to esterify the acid chloride. The ester is then recovered by distillation. ii. 5' -Dimethoxytrityl-2' -O- (ethoxycarbonyl- ethyl)uridine Phosphoramidite Uridine is blocked and then treated with Ag 2 0 and α- cloroethoxycarbonylethane as per the procedure of Example 2-A- iii to yield the title compound. iii. 5' -Dimethoxytrityl-2' -0- (eth-2-ylhydr- azide)uridine Phosphoramidite 5' -Dimethoxytrityl-2' -0- (ethoxycarbonylethyl)uridine phosphoramidite will be treated with hydrazine to give the corresponding 2' -0- (ethylhydrazide)uridine title compound. I. Preparation of 5' -Dimethoxytrityl-2' -O- (Alcohol FunctionalizedSpace-spanningGroup)NucleosidePhosphoramidites i. 1-0- (Tetrahydropyran-2-yl) -7-bromoheptanol 7-Bromoheptanol will be treated with dihydropyrane in the presence of acid to give 1-0- (tetrahydropyran-2-yl) -7- bromoheptanol. ii. 5' -Dimethoxytrityl-2' -O- [O- (Tetrahydropyran- 2-yl)heptan-7-ol) ] -N4-Benzylcytidine Phosphoramidite Cytidine will be treated with 1-0- (tetrahydropyran-2- yl) -7-bromoheptanol as per the procedure of Example 2-A-ii to give the title compound. iii. 5' -Dimethoxytrityl-2' -O- [O- (Tetrahydro- pyran-2-yl)heptan-7-ol) ]uridine Phosphoramidite Uridine is blocked and then treated with Ag 2 0 and 1-0- (tetrahydropyran-2-yl) -8-bromoheptanol as per the procedure of Example 2-A-iii to give the title compound. J. Preparation of 5' -Dimethoxytrityl-2' -0 or 2'-S (Thiol Functionalized Space-spanning Group) -Nucleoside Phosphoramidites i. Via Ring Opening of 2,2'-Anhydro Pyri idines a. 2' -S- (Octan-8-Thiol) thymidine 2,2'-Anhydro thymidine will be ring opened with octane-1, 8-dithiol to give 2' -S- (octan-8-thiol) thymidine. b. 5' -Dimethoxytrityl-2 -S- [S-Trityl- (Octan-8-thiol)] -2 ' -Deoxy-Thymidine Phosphoramidite 2' -S- (octan-8-thiol) thymidine when treated with trityl chloride will give 2' -S- [S-trityl (octan-8-thiol) ] thymi¬ dine which will then be further treated with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position and finally phosphitylation as per Example 2-A-v to give the title compound. ii. Via O-Alkylation a. l-S-Trityl-8-Bromohexanethiol 8-Bromohexanethiol will be tritylated with trityl chloride to give l-S-trityl-8-bromohexanethiol. b. 5'-Dimethoxytrityl-2'-0- [S-Trityl- (Hexan-8-thiol) ] -N6-Benzyladenosine Phosphoramidite Adenosine is treated with NaH in DMF as per example 2-A-i. The reaction product will then be treated with 1-S- trityl-8-bromohexanethiol followed by treatment with (CH 3 ) 3 SiCl, Ph-C(0)-Cl and NH 4 0H to yield the N6-benzyl protected 2'-0-[S- trityl (hexyl-8-thiol) ] functionalized adenosine. Treatment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' - position followed by phosphitylation, further as per the procedure of Example 2-A-i, will give the title compound. c. 5'-Dimethoxytrityl-2'-0- [S-Trityl- (Hexan-8-thiol) ]uridine Phosphoramidite Uridine is blocked and then treated with Ag 2 0 and 1-S- trityl-8-bromohexanethiol as per Example 2-A-iii. The reaction product will then be treated with followed by treatment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position and finally phosphitylation, further as per the procedure of Example 2-A-iii, to give the title compound. d. 1-S-Trityl-8-Bromopentanethiol 8-Bromopentanethiol will be tritylated with trityl chloride to give 1-S-trityl-8-bromopentanethiol. e. 5' -Dimethoxytrityl-2' -O- [S-Trityl- (Pentan-8-thiol) ]uridine Phosphoramidite Uridine is blocked and then treated .with Ag 2 0 and 1-S- trityl-8-bromopentanethiol as per Example 2-A-iii followed by treatment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position and finally phosphitylation, further as per the procedure of Example 2-A-iii, to give the title compound. K. Preparation of 5' -Dimethoxytrityl-2' -O- (Protected Aldehyde Functionalized Space-spanning Group)Nucleoside Phosphoramidites i. Preparation of Acetal Functionalization a. N6-Benzyl-5'-Dimethoxytrityl-2' -O- [Propion-3-al Bis(o-Nitrobenzyl Acetal)adenosine Phosphor¬ amidite Adenosine is treated with NaH and 3-bromopropion- aldehyde bis (o-nitrobenzyl) acetal as per the procedure of Example 2-A-i. Further treatment with (CH 3 ) 3 SiCl, Ph-C(0)-Cl and NH 4 OH to add a benzyl blocking group followed by DIPA and CH 2 C1 2 to add a DMT blocking group at the 5'-position and further followed by phosphitylation as per the procedure of Example 2-A-i, will give the desired compound. b. 5" -Dimethoxytrityl-2" -O- [Propion-3-al Bis (o-Nitrobenzyl Acetal)uridine Phosphoramidite Uridine is blocked followed by treatment with Ag 2 0 and 3-bromopropionaldehyde bis (o-nitrobenzyl) acetal as per the procedure of Example 2-A-iii. Further treatment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position and further followed by phosphitylation as per the procedure of Example 2-A-i, will give the desired compound. ii 6- (Diphenylimidazolidino)hexyl Bromide 6-Bromohexionyl acid chloride will be treated with ethylmercaptan. The resulting ethyl thiol-6-bromohexionate is then desulfurized with Raney nickel giving 6-bromohexenal . The 6-bromohexenal is then treated with 1,2-dianilinoethylene in benzene/DMSO to give the title 6- (diphenylimidazolidino) hexyl bromide. iii. 5' -Dimethoxytrityl -2 ' -O- [6- (diphenylimid¬ azolidino)hexyl] -N2-Isobutyrylguanosine Phosphoramidite 3' ,5' -0- (Tetraisopropyldisiloxane-l,3-diyl) -2-chloro- 6- (2, 6-dichlorophenoxy)purine riboside is reacted with 6- (di- phenylimidazolidino)hexyl bromide as per Example 2-A-iv. Further treatment with (CH 3 ) 3 SiCl, isobutyryl chloride and NH 4 OH will yield N2-isobutyryl protected 2' - (diphenyl¬ imidazolidino)hexyl functionalized guanosine. Treatment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position followed by phosphitylation, further as per the procedure of Example 2-A-iv, will give the title compound. iv. 5' -Dimethoxytrityl -2 ' -O- [6- (diphenylim¬ idazolidino)hexyl] -N6-Benzyladenosine Phosphoramidite Adenosine is treated with NaH/DMF followed by treatment with 6- (diphenylimidazolidino)hexyl bromide as per Example 2-A-i. Further treatment with (CH 3 ) 3 SiCl, benzyl chloride and NH 4 OH will yield N6-benzyl protected 2'- (diphenylimidazolidino) hexyl functionalized adenosine. Treat¬ ment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' - position followed by phosphitylation, further as per the procedure of Example 2-A-i, will give the title compound. v. 5'-Dimethoxytrityl-2 r -0- [6- (diphenylimidazol¬ idino)hexyl) -N4-Benzylcytidine Phosphoramidite Cytidine is treated with NaH/DMF followed by treatment with 6- (diphenylimidazolidino)hexyl bromide as per Example 2-A- ii. Further treatment with (CH 3 ) 3 SiCl, benzyl chloride and NH 4 0H will yield N4-benzyl protected 2 ' - (diphenylimidazolidino)hexyl functionalized cytidine. Treat¬ ment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5 ' - position followed by phosphitylation, further as per the procedure of Example 2-A-ii, will give the title compound. vi. 5' -Dimethoxytrityl-2 r -0- [6- (diphenylim¬ idazolidino)hexyl]uridine Phosphoramidite Uridine is blocked and then treated with Ag 2 0 and 6- (diphenylimidazolidino) hexyl bromide as per Example 2-A-iii. Treatment with DIPA and CH 2 C1 2 to add a DMT blocking group at the 5' -position followed by phosphitylation, further as per the procedure of Example 2-A-ii, will give the titled compound. EXAMPLE 3 Preparation Of Oligonucleotides Having An Abasic Sites Located Thereon A. Preparation of An Abasic Site Containing Oligo¬ nucleotide Via Enzymatic Reaction i. Oligonucleotide Containing Single Uridine Site An oligonucleotide of the sequence: Oligomer 1 CGC AGU * CAG CC wherein U * represents a 2'-deoxy uridine nucleotide, was prepared utilizing the procedure of Example 1. The deoxyuridine nucleotide in the middle of the sequence was added during the synthesis utilizing deoxyuridine phosphoramidite (Glen Research, Sterling, VA) . The oligonucleotide was prepared utilizing standard synthesis cycles. It was deprotected by normal deprotection utilizing ammonium hydroxide, 30%, for 16 hours. The solvent was evaporated, and the residue was purified by HPLC and detritylated. Final purification was effected on Sephadex G-25. ii. Enzyme Stock Solution Preparation Uracil-DNA glycosylase was isolated from E. coli M5219 cells transformed with the expression plasmid pBD396 containing the ung gene. The enzyme was purified to electrophoretic homogeneity as described by Lindahl, et al . , J. Biol . Chem . , 1977, 252, 3286, and stored in 30 Mm HEPES-NaOH, pH 7.4, containing 5% glycerol, 2 mM DTT and 1 mM EDTA. iii. Oligonucleotide Containing Single Abasic Site An abasic oligonucleotide of the sequence: Oligomer 2 CGC AGD * CAG CC wherein D * represents an abasic site, was prepared by treating 237 O.D. units of Oligomer 1 of Example 3-A-i in 0.5 ml water with 200 μl of the stock solution of Example 3-A-ii (200 micrograms of uracil DNA-glycosylase) and incubating at room temperature overnight. HPLC analysis showed quantitative removal of uracil as indicated by a 1:10 ratio between uracil and the abasic dodecamer oligonucleotide. The uracil retention time was 2.43 mins and the abasic oligonucleotide was 21.68 mins. The solution was lyophilized and stored in the freezer until further use. iv. Oligonucleotide Containing Multiple Uridine Sites In the manner of Example 3-A-i the following oligo- nucleotide was prepared: Oligomer 3 GAC AGA GGU * AGG AGA AGU * GA wherein U * represents a 2' -deoxyuridine nucleotide. The oligo¬ nucleotide when treated as per the procedure of Example 3-A-iii will give an oligonucleotide of the sequence Oligomer 4 GAC AGA GGD * AGG AGA AGD * GA wherein D * represents an abasic site within the oligo¬ nucleotide. B. Preparation of An Abasic Site Containing Oligo¬ nucleotide Via Abasic Sugar Precursor i. 5-0-4,4' -Dimethoxytrityl-1,2-Dideoxy-D- Ribofuranose-3-0- (2-Cyanoethyl-N,N' -Diisopropyl) Phos- phoramidite 5-0-4,4' -Dimethoxytrityl-1,2-dideoxy-D-ribofuranose-3- 0- (2-cyanoethyl-N,N' -diisopropyl) phosphoramidite is prepared as per the procedure of Lyer, et al., Nucleic Acids Research, 1990, 18, 2855, or as per the procedure of Didier Peoch et al . , Tetrahedron Letters, 1991, 32, 207. ii. Oligonucleotide Containing Abasic Site Oligomer 2 of Example 3-A-iii, i.e. the oligonuc¬ leotide of the sequence: Oligomer 2 CGC AGD * CAG CC wherein D * represents an abasic site, can also be prepared utilizing the synthetic procedures of the papers identified in Example 3-B-i. Utilizing those procedures, an o-Nitro- benzyldeoxyfuranose containing oligonucleotide is synthesized using the oligonucleotide synthetic methods of these papers. Photolysis, utilizing a high intensity Hg lamp, generates the corresponding abasic site containing oligonucleotide. Such abasic oligonucleotides are also described by Horn, et al . , Nucleosides & Nucleotides, 1991, 10, 299. EXAMPLE 4 Preparation of Oligonucleotides Incorporating 2' -0- (Amine Functionalized Space-spanning Group) A. Single Site An oligonucleotide of the sequence: Oligomer 5 GGC TGA * CTG CG wherein A * indicates a 2' -O- (pentylamino) adenosine nucleotide was prepared as per the procedure of Example 1 utilizing an extend coupling time of 10 minutes during the coupling step of the modifiednucleotide unit. 5' -Dimethoxytrityl-2' -O- (pentyl- N-phthalimido) -N6-benzyladenosinephosphoramidite (fromExample 2-A-i was utilized in the DNA synthesizer as a 0.09M solution in anhydrous CH 3 CN. Oligonucleotide synthesis was carried out in either an ABI 39OB or 394 synthesizer employing the standard synthesis cycles with an extended coupling time of 10 minutes during coupling of the 5' -dimethoxytrityl-2' -0- (pentyl- N-phthalimido) -N6-benzyladenosine phosphoramidite into the oligonucleotide sequence. Coupling efficiency of > 98% was observed for the 5' -dimethoxytrityl-2' -0- (pentyl-N-phthal¬ imido) -N6-benzyladenosine phosphoramidite coupling. Removal of the N-phthalimido amine protecting group is effected simultaneously with NH 4 0H deprotection of the benzyl and isobutyryl nucleotide base blocking groups. B. Multiple Sites An oligonucleotide of the sequence: Oligomer 6 CTG TCT CCA * TCC TCT TCA * CT wherein A * represents a nucleotide modified to incorporate a pentylamino functionality was prepared as per the procedures of Example 4-A. This oligonucleotide is an antisense compound to the E2 region of the bovine papilloma virus-1 (BPV-1) . EXAMPLE 5 A. Coupling of Oligonucleotide Strand Having An Abasic Site To An Oligonucleotide Having An Amine Func¬ tionalized Space-spanning Group Two stranded, duplexed, cross-linked oligonucleotides of the structure: Cross-linked Strands I where " | " represents an O- (CH 2 ) 5 -N-CH 2 - cross-linkage between the oligonucleotide strands is prepared by reacting 2.8 O.D. units of Oligomer 5, i.e. the GGC TGA * CTG CG oligonucleotide of Example 4-A, in 100 μl of 0.2 M NaOAc buffer (pH 5.02) with 2.37 O.D. units of Oligomer 2, i.e. the abasic oligonucleotide CGC AGD * CAG CC of Example 3-A-iii, dissolved in 10 μl of water. The combined solution was let stand for 2 hours. 10 mg of NaCNBH 3 was dissolved in 400 μl of 250 mM NaOAc (pH 5.02) and 25 μl of this solution was added to the reaction solution. After this addition, the final concentration of the cyanoboro- hydride in the solution was nearly 80 mM. The reaction was followed at 1 hr intervals by HPLC. The amine linked oligonucleotide had a retention time of 21.65 mins and the abasic oligonucleotide 22.46 mins. A product peak was observed at 24.07 mins. A slow increase in the product peak was observed. After 12 hrs the product was separated from the reaction mixture by HPLC yielding 1.05 O.D. units, 20.3%. A small aliquot of the product was re-injected into the HPLC column and observed as a single peak. B. Gel Analysis A gel analysis was carried out on the above cross- linked 11 mer oligonucleotides, i.e. Cross-linked Strands I. The cross linked material moved slower than either of its component 11 mer oligonucleotides, i.e. Oligomers 2 or 5. Indeed it had the same electrophoretic mobility as that of a 21 mer oligonucleotide (11 + 11 -1 for the loss of a base) . C. Ion Exchange Chromatography Cross-linking of the Cross-linked Strands I was further confirmed by using ion exchange chromatography. The 21 mer cross-linked strands, since they have the greatest amount of charge, were eluted at 0.25 M salt concentration whereas the 11 mer components oligonucleotides were eluted at 0.15M salt concentration. D. Cross-Linking Affirmation Cross-linking as opposed to hybridization duplex formation was confirmed independently by gel analysis and by re-injection of the cross-linked strands into HPLC. Gel analysis of a mixture the two component oligonucleotides mixed together without cross-linking did not yield the 21 mer mobility product. Re-injection of the cross-linked product into HPLC did not produce an equilibrium mixture of the two single oligonucleotide strands but came out as a single peak. EXAMPLE 6 Preparation of Oligonucleotide Having Sulfur Linking Atom Attaching An Amine Functionalized Space-spanning Groups Thereon An oligonucleotide of the sequence: Oligomer 7 GGC T * GA CTG CG wherein T * represents a nucleotide modified to incorporate a dodecylamino functionality joined to the thymidine nucleotide via a sulfur linking atom will be prepared as per the procedure of Example 4-A utilizing the oligonucleotide of Example 2-B-ii. EXAMPLE 7 Preparation of Oligonucleotide Having Nitrogen Linking Atom Attaching An Amine Functionalized Space-spanning Groups Thereon An oligonucleotide of the sequence: Oligomer 8 GGC TGA * CTG CG wherein A * represents a nucleotide modified to incorporate a butylamino functionality joined to the adenosine nucleotide via a nitrogen linking atom will be prepared as per the procedure of Example 4-A utilizing the oligonucleotide of Example 2-C-ii. EXAMPLE 8 Preparation of Oligonucleotide Having Carbon Linking Atom Attaching An Amine Functionalized Space-spanning Groups Thereon An oligonucleotide of the sequence: Oligomer 9 GGC TGA * CTG CG wherein A * represents a nucleotide modified to incorporate a allylamine functionality joined to the adenosine nucleotide via a methylene linking atom will be prepared as per the procedure of Example 4-A utilizing the oligonucleotide of Example 2-D-i. EXAMPLE 9 A. Coupling of Oligonucleotide Strands Via Abasic Site and Amine Functionalized Space-spanning Group Connecting Through A Sulfur Linking Group Two stranded, duplexed, cross-linked oligonucleotides of the structure: Cross-linked Strands II where " | " indicates represents an S- (CH 2 ) 12 -N-CH 2 - cross- linkage between the individual oligonucleotides of the structure will be prepared by reacting Oligomer 7 of Example 6 with the abasic Oligomer 2 of Example 3-A-iii utilizing the procedure of Example 5-A. B. Coupling of Oligonucleotide Strands Via Abasic Site and Amine Functionalized Space-spanning Group Connecting Through A Nitrogen Linking Group Two stranded, duplexed, cross-linked oligonucleotides of the structure: Cross-linked Strands III GGC AGD CAG CC GGC TGA CTG CG where " | " indicates represents an -NH- (CH 2 ) 4 -N-CH 2 - cross- linkage between the individual oligonucleotides of the structure will be prepared by reacting Oligomer 8 of Example 7 with the abasic Oligomer 2 of Example 3-A-iii utilizing the procedure of Example 5-A. C. Coupling of Oligonucleotide Strands Via Abasic Site and Amine Functionalized Space-spanning Group Connecting Through A Methylene Linking Group Two stranded, duplexed, cross-linked oligonucleotides of the structure: Cross-linked Strands IV where " | " indicates represents an -CH 2 -CH=CH-N-CH 2 - cross- linkage between the individual oligonucleotides of the structure will be prepared by reacting Oligomer 9 of Example 8 with the abasic Oligomer 2 of Example 3-A-iii utilizing the procedure of Example 5-A. EXAMPLE 10 A. Preparation of Oligonucleotide Having A Hydrazine Functionalized Space-spanning Groups Thereon i. Single Functionality An oligonucleotide of the sequence: Oligomer 10 GGC TGU * CTG CG wherein U * represents a nucleotide modified to incorporate a 2' -0- (octylhydrazino) functionality joined to the uridine nucleotide will be prepared as per the procedure of Example 4-A utilizing the oligonucleotide of Example 2-E-ii followed by deblocking of the benzylcarbazide protecting group via hydrogenolysis in the presence of palladium on charcoal. ii. Multiple Functionalities An oligonucleotide of the structure: Oligomer 11 AGC CAG AU * C U GA GCC UGG G ** AG CUC UCU GGC U wherein U * represents an uridine nucleotide having a 2'-0- (octylhydrazine) group thereon and G ** represents a guanosine nucleotide having a 2'-0- (octylhydrazine) group thereon will be prepared as per the procedure of Example 4-A utilizing the nucleotides of Examples 2-E-ii and 2-E-iv, respectively, to introduce the hydrazine functionalized space-spanning group containing nucleotides in the proper sequence. Deblocking of the benzylcarbazide protecting group is effected via hydrogenolysis in the presence of palladium on charcoal. B. Preparation of Oligonucleotide Having A Hydroxyl¬ amine Functionalized Space-spanning Groups Thereon An oligonucleotide of the sequence: Oligomer 12 GGC TGU * CTG CG wherein U * represents a nucleotide modified to incorporate a octyl-hydroxyl mine functionality joined to the cytidine nucleotide via an oxygen linking atom will be prepared as per the procedure of Example 4-A utilizing the oligonucleotide of Example 2-F-iii followed by treatment of the O-phthalimide group with methylhydrazine in DCM to generate the hydroxylamine functionality on the octyl space-spanning group. C. Preparation of Oligonucleotide Having A Semicarb¬ azide Functionalized Space-spanning Groups Thereon An oligonucleotide of the sequence: Oligomer 13 GGC TGU * CTG CG wherein U * represents a nucleotide modified to incorporate a pentyl-N-semicarbazide functionality joined to the uridine nucleotide via an oxygen linking atom will be prepared as per the procedure of Example 4-A utilizing the oligonucleotide of Example 2-G-i. D. Preparation of Oligonucleotide Having A Hydrazide Functionalized Space-spanning Groups Thereon An oligonucleotide of the sequence: Oligomer 14 GGC TGU * CTG CG wherein U * represents a nucleotide modified to incorporate an ethyl hydrazide functionality joined to the uridine nucleotide via an oxygen linking atom will be prepared as per the pro¬ cedure of Example -A utilizing the oligonucleotide of Example 2-H-iii. E. Preparation of Oligonucleotide Having An Alcohol Functionalized Space-spanning Groups Thereon An oligonucleotide of the sequence: Oligomer 15 GGC TGU * CTG CG wherein U * represents a nucleotide modified to incorporate a heptan-7-ol functionality joined to the uridine nucleotide will be prepared as per the procedure of Example 4-A utilizing the oligonucleotide of Example 2-I-iii. EXAMPLE 11 A. Coupling of Oligonucleotide Strands Via Abasic Site and Hydrazine or Hydrazone Functionalized Space-spanning Group i. Hydrazine Linked Strands Two stranded, duplexed, cross-linked oligonucleotides of the.structure: Cross-linked Strands V GGC AGD CAG CC GGC TGU I CTG CG where " | " indicates represents an O- (CH 2 ) 8 -NH-NH-CH 2 - cross- linkage between the individual oligonucleotides of the structure will be prepared by reacting Oligomer 10 of Example 10-A-i with the abasic Oligomer 2 of Example 3-A-iii followed by reduction of the resulting hydrazone linkage with NaCNBH 3 in NaOAc buffer as per the procedure of Example 5-A to form the hydrazine linkage. ii. Hydrazone Linked Strands The cross-linker strands of Example 13-A-i having a hydrazone cross-linkage can be formed by omitting the NaCNBH 3 reduction step of Example 13-A-i. B. Coupling of Oligonucleotide Strands Via Abasic Site and Hydroxylamine or Oxime Functionalized Space-spanning Group i. Hydroxylamine Linked Strands Two stranded, duplexed, cross-linked oligonucleotides of the structure: Cross-linked Strands VI GGC AGD CAG CC GGC TGU CTG CG where " | " indicates represents an O- (CH 2 ) 8 -NH-0-CH 2 - cross- linkage between the individual oligonucleotides of the structure will be prepared by reacting Oligomer 12 of Example 10-B with the abasic Oligomer 2 of Example 3-A-iii followed by reduction of the resulting oxime linkage with NaCNBH 3 in NaOAc buffer as per the procedure of Example 5-A to form the hydroxylamine. ii. Oxime Linked Strands The cross-linker strands of Example 13-B-i having an oxime cross-linkage can be formed by omitting the NaCNBH 3 reduction step of Example 13-A-i. C. Coupling of Oligonucleotide Strands Via Abasic Site and Semicarbazide or Semicarbazone Functionalized Space- spanning Group i. Semicarbazide Linked Strands Two stranded, duplexed, cross-linked oligonucleotides of the structure: Cross-linked Strands VII where " [ " indicates represents an O- (CH 2 ) 8 -NH-NH-CH 2 - cross- linkage between the individual oligonucleotides of the structure will be prepared by reacting Oligomer 13 of Example 10-C with the abasic Oligomer 2 of Example 3-A-iii followed by reduction of the resulting semicarbazone linkage with NaCNBH 3 in NaOAc buffer as per the procedure of Example 5-A to form the semicarbazide linkage. ii. Semicarbazone Linked Strands The cross-linker strands of Example 13-A-i having a semicarbazone cross-linkage can be formed by omitting the NaCNBH 3 reduction step of Example 13-A-i. D. Coupling of Oligonucleotide Strands Via Hemiacetal Linkage Across An Abasic Site and An Alcohol Functionalized Space-spanning Group Two stranded, duplexed, cross-linked oligonucleotides of the structure: Cross-linked Strands VIII where " | " indicates represents an O- (CH 2 ) 7 -0-CH(OH) - cross- linkage between the individual oligonucleotides of the structure will be prepared by reacting Oligomer 15 of Example 10-E with the abasic Oligomer 2 of Example 3-A-iii in the presence of trifluoroacetic acid utilizing a modification of the procedure of Knorre, et al . , "Nucleotide and Oligonucleotide Derivatives As Enzyme and Nucleic Acid Targeted Irreversible Inhibitors", Chemical Aspects, G. Weber (Ed.), Advance Press, Oxford, 1986, pp. 277-320. EXAMPLE 12 Preparation of Oligonucleotide Having Multiple Space-spanning Groups That Include The Same Or Different Functionalities Thereon A. Aldehyde and Amine Functionality Containing Oligo¬ nucleotide A oligonucleotide of the structure: Oligomer 16 AGC CAG AUC UGA * GCC UGG GAG CU ** C UCU GGC U wherein A * represents an adenosine nucleotide having a 2'-0- (pentylamino) group thereon and U ** represents a uridine nucleotide having a 2' -O- [propion-4-al bis (o-nitrobenzyl) acetal] group thereon will be prepared as per the procedure of Example 4-A utilizing the nucleotides of Examples 2-A-i and 2- K-i-b, respectively, for the functionalized space-spanning group containing nucleotides. B. Multiple Thiol Functionality Containing Oligonuc¬ leotide A oligonucleotide of the structure: Oligomer 17 A * GC CAG AUC U GA GCC UGG GAG CUC UCU GGC U ** wherein A * represents an adenosine nucleotide having a 2'-0- [S- trityl(hexyl-8-thiol)] group thereon and U ** represents a uridine nucleotide having a 2'-0- [S-trityl (hexyl-8-thiol) ] group thereon will be prepared as per the procedure of Example 4-A utilizing the nucleotides of Examples 2-J-ii-b and 2-J-ii- c, respectively, for the functionalized space-spanning group containing nucleotides. C. Multiple Aldehydic Functionality Containing Oligonucleotide An oligonucleotide of the structure: Oligomer 18 GAC AGA GGU * AGG AGA AU * GA wherein U * is a 2' -O- [propion-3-al bis (o-nitrobenzyl) acetal] group will be prepared as per the procedure of Example 4-A utilizing the nucleotide of Example 2-K-i-b for the aldehydic functionalized space-spanning group containing nucleotides. D. Thiol and Amine Functionality Containing Oligo¬ nucleotide A oligonucleotide of the structure: Oligomer 19 AGC CAG * AUC U GA GCC UGG GAG CUC U ** CU GGC U wherein G * represents an guanosine nucleotide having a 2'-0- ( [2-amylenyl] -N-phthalimide) group thereon and U ** represents a uridine nucleotide having a 2'-0- [S-trityl(pentan-8-thiol) ] group thereon will be prepared as per the procedure of Example 4-A utilizing the nucleotides of Examples 2-A-iv and 2-J-ii-e, respectively, for the functionalized space-spanning group containing nucleotides. EXAMPLE 13 Multi-Site Cross-Linking Of Dual Strands of Oligonucleotides A. Cross-Linking Via Dual Abasic Sites Two stranded duplexed, multi-site cross-linked oligonucleotides of the structure: Cross-linked Strand IX CTG TCT CCA TCC TCT TCA CT GAC AGA GGD I AGG AGA AGDI GA wherein " | " represents a cross-linkage between the strands, are prepared from Oligomer 4 from Example 3-A-iv and Oligomer 6 from Example 4-B utilizing the cross-linking procedure of Example 5-A. The resulting cross-linked strands are held together not only by hybridization of the duplex structures but also by the dual cross-linkages extending between the individual oligonucleotide strands. B. Via Dual Space-spanning Groups Two stranded duplexed, multi-site cross-linked oligonucleotides of the structure: Cross-linked Strands X CTG TCT CCA TCC TCT TCA CT GAC AGA GGU I AGG AGA AGUI GA wherein " | " represents a cross-linkage having a covalent bond formed via an oxime linkage between the strands, is prepared from Oligomer 18 from Example 12-C and Oligomer 6 from Example 4-B. A solution of Oligomer 18 in water will be treated with hydrazine hydrate/ sodium cyanoborohydride to remove the aldehydic protecting groups. Oligomer 6 is then added in 0.1 M NaCl to hybridize the strands. Sodium acetate buffer is then added to effect cross-linking of the strands via formation of Schiff's bases between the amine and aldehyde groups. NaCNBH 3 is added to reduced the oxime linkage to an amine linkage whereby the resulting cross-linked strands will be held together not only by hybridization of the duplex structures but also by the multiple cross-links extending between the individual oligonucleotide strands. EXAMPLE 14 Coupling of Two Sites on Single Strand A single strand duplexed, cross-linked, hairpin loop oligonucleotide of the structure: Cross-linked Strand XI C U U C U AGCCAGA GAGC G UCGGUCU CUCG G A G wherein " | " represents a cross-linkage having a covalent bon formed via an oxime linkage between the regions of the strand, is prepared from Oligomer 16 from Example 12-A. Oligomer 16 is taken up in 0.1 M NaCl solution to effect hybridization an then treated With hydrogen in the presence of palladium o charcoal at atmospheric pressure until two equivalents of hydrogen are taken up indicating removal of the aldehydi protecting groups. Sodium acetate buffer is then added t effect the formation of a Schiff's base linkage between th amine and aldehyde groups. NaCNBH 3 is added to reduced th oxime linkage to an amine linkage whereby the resulting cross linked strand will be held together not only by hybridizatio of the duplex stem portion of the hairpin loop structure bu also by the covalent cross-linkage extending across the ste nucleotides. EXAMPLE 15 Coupling Via Disulfide Linkage A single strand of duplexed, cross-linked, bulged, hairpin loop oligonucleotide of the structure: Cross-linked Strand XII C U U C U AGCCAGA GAGC G U ICGGUCU CUCG G A G wherein " [ " represents a cross-linkage having a covalent bond formed via a disulfide linkage between the regions of the strand, is prepared from Oligomer 17 from Example 12-B. Oligomer 17 will be soiubilized in 0.1 M NaCl solution under nitrogen to effect hybridization and then treated with silver nitrate to remove the S-trityl protecting groups. A disulfide bond is formed between the two free thiol groups via mild oxidation by bubbling air through the solution to cross- linkage the A-U site of the oligonucleotide. The oligonucle¬ otide will be held in the hairpin loop structure not only by hybridization of the duplexed stem portions of the hairpin loop structure but also by the covalent disulfide bond connecting the stem regions. EXAMPLE 16 Coupling Via Dialdehyde Utilizing the procedure of Example 4-A an oligonuc¬ leotide of the sequence: Oligomer 20 A * GC CAG AUC U GA GCC UGG GAG CUC UCU GGC U wherein A * is a 2' -O- (eicosylamino) adenosine nucleo¬ tide of Example 2-A-ii-c is prepared. The oligonucleotide is removed from the CPG synthetic column and de-salted on Sephadex G-25 Oligomer 20 will then be treated as per the peroxidation procedure of Lemairte et. al., Proc. Natl . Acad. Sci . USA, 84:648 ' (1986) to effect periodate-oxidation of the sugar moiety of the 3' terminus uridine nucleotide. A single strand of duplexed, cross-linked, hairpin loop oligonucleotide of the structure: Cross-linked Strand XIII C U U C U AGCCAGA GAGC G U ICGGUCU CUCG G A G wherein " | " represents a covalent cross-linkage formed via the oxidized, ring opened sugar of the 3'-terminal nucleotide and the amine group on the opposing nucleotide of the duplexed stem portion of the strand. Such cross-linkage is formed from the periodate-oxidized oligonucleotide by solubilizing the oxidized oligonucleotide in 0.1 M NaCl to effect hybridization followed by the addition of sodium acetate buffer and NaCNBH 3 . As the intermediate Schiff's base cross-linkage is formed, it is reduced to an amine linkage by the addition of NaCNBH 3 as per the procedure of Example 5-A. EXAMPLE 17 Coupling Via Acetal Linkage Utilizing the procedure of Example 4 an oligonucleo¬ tide of the sequence: Oligomer 20 A * GC CAG AUC U GA GCC UGG GAG CUC UCU GGC U wherein A * is a 2' -O- [propion-3-al bis (o-nitrobenzyl) acetal] functionalized adenosine nucleotide will be prepared as per the procedure of Example 4-A utilizing the nucleotide of Example 2- K-i-a to introduce the aldehydic functionalized space-spanning group containing nucleotide with the oligonucleotide sequence. The oligonucleotide is removed from the CPG synthetic column and de-salted on Sephadex G-25. A single strand of duplexed, cross-linked, hairpin loop oligonucleotide of the structure: Cross-linked Strand XIV C U U C U AGCCAGA GAGC G U ICGGUCU CUCG G A G wherein " [ " represents an acetal cross-linkage formed between the 2',3' -hydroxyl moieties of the sugar on the 3'-terminal U nucleotide and the aldehydic functionality on the opposing A nucleotide of the duplexed stem portion of the strand, is prepared by effecting cross-linking in 0.1 M NaCl in the presence of trifluoroacetic acid. This procedure is a modification of the procedure of Knorre et. al. , "Nucleotide and Oligonucleotide Derivatives As Enzyme and Nucleic Acid Targeted Irreversible Inhibitors", Chemical Aspects, G. Weber (Ed.), Advance Press, Oxford, 1986, pp. 277-320. Upon reaction of the free aldehydic group on the A nucleotide, cross-linking to the opposing 2',3' -hydroxyl' s of the 3'-terminus U nucleoside will yield a covalent cross-linkage between nucleotides of the stem portion of the hairpin loop bulged single stranded oligonucleotide. EXAMPLE 18 Coupling Via Heterobifunctional Linker on Single Strand A single strand of duplexed, cross-linked, hairpin loop oligonucleotide of the structure: Cross-linked Strand XV C U U C U AGCCAGA GAGC G \ UCGGUCU CUCG G A G wherein •■ \ " represents a cross-linkage formed via a homobifunctional linker between the G and U nucleotides of duplexed regions of the strand across the G and U nucleotides of the two separate regions that are one base removed from Wat¬ son/Crick base pairs, is prepared from Oligomer 19 from Example 12-D. The Oligomer 19 will first be taken up in a 0.1M NaCl solution to effect hybridization of the oligonucleotide into a hairpin loop single strand duplexed structure. The reaction solution is then treated with silver nitrate in buffer to remove the S-trityl blocking group. A aliquot of N- succinimidyl 3- (2-pyridyldithio)propionate (SPDP) (Pierce, Rockford, II) in weak alkaline is added to effect coupling of the amine functionality to the linker. The pH is then adjusted to pH 4.5 to effect exchange of the 2-pyridyl-disulfide and the thiol functionality on the oligonucleotide and in doing so to effect cross-linking of the strand. The strand will thus be held together not only by hybridization of the duplex stem portion of the hairpin loop bulged structure but also by the heterobifunctional cross-linker extending across the stem nucleotides. EXAMPLE 19 Coupling Via Homobifunctional Linker A single strand of duplexed, cross-linked, bulged, hairpin loop oligonucleotide of the structure: Cross-linked Strand XVI C U x U C U AGCCAGA GAGC G UCGGUCU CUCG G A G x wherein a cross-linkage is formed via a homobifunctional linke spanning between the U nucleotide on the UCU bulge and the G nucleotide of the AGGGUC loop regions of the strand, is prepared from Oligomer 11 from Example 10-A-ii. Molecula models of the proposed tertiary structure of Strand XVI indicate that the U x and G x nucleotides lie in close physical proximity to each other. To prepare Strand XVI the Oligomer 1 will first be taken up in a 0.1M NaCl solution to effec hybridization of the oligonucleotide into a hairpin loop bulge single strand duplexed structure. The reaction solution i then adjusted to be a 0.2 M sodium borate buffer. Disucσinimidyl suberate (DSS, Pierce, Rockford, II) is added t effect cross-linking of the hydrazine reactive functionalitie of the uridine-guanosine nucleotides. The U nucleotide of th bulge and G nucleotide of the loop are linked via hydrazid linkages between the functionalities on the space-spanning groups and the homobifunctional cross-linker. In this structure, the U x nucleotide of the interior loop and the G x nucleotide of the hairpin loop are neither complementary to nor hybridizable with one another but they are located in 3- dimensional space in proximity with each other because of the higher order structure of the oligonucleotide. The cross- linkage spans this 3-dimensional space to fix the oligonucleotide in the higher order structure. * Example 20 Synthesis of Uridine -2 ' -hexyl Aminolinker Preparation of 5'-dimethoxytrityl-2' - (O-hexyl-N- phthalimido) uridine phosphoramidite 2' ,3' -O-Dibutyl stannylene-uridine was synthesized according to the procedure of Wagner, et al . , J. Org. Chem. , 1974, 39, 24. This compound was dried over P 2 0 5 under vacuum for 12 hrs. To a solution of this compound (29 g, 42.1 mmols) in 200 ml of anhydrous DMF were added (16.8 g, 50 mmols) of 6- bromohexyl phthalimide and 4.5 g of sodium iodide and the mixture was heated at 130°C for 16 hrs. under argon. The reaction mixture was evaporated, co-evaporated once with toluene and the gummy tar residue was applied on a silica column (500 g) . The column was washed with 2L of EtOAc followed by eluting with 10% MeOH:90% EtOAc. The product, 2'- and 3'-isomers of O-hexyl-Ω-N-phthalimido uridine, eluted as an inseparable mixture (R f =0.64 in 10% MeOH in EtOAc) . By 13 C NMR, the isomeric ratio was ca. 55% of the 2' isomer and ca. 45% of the 3' isomer. The combined yield was 9.2 g (46.2%) . This mixture was dried under vacuum and re-evaporated twice with pyridine. It was dissolved in 150 mL anhydrous pyridine and treated with 7.5 g of dimethyoxytrityl chloride (22.13 mmols) and 500 mg of DMAP. After 2 hrs. TLC (6:4 EtOAc:Hexane) indicated complete disappearance of the starting material and a good separation between 2' and 3' isomers (R f =0.29 for the 2' isomer and 0.12 for the 3' isomer) . The reaction mixture was quenched by the addition of 5ML of CH,0H and evaporated under reduced pressure. The residue was dissolved in 300mL CH 2 C1 2 , washed successively with saturate NaHC03* followed by saturated NaCl solution. It was dried (MgS0 4 ) and evaporated to give 15 g of a brown foam which was purified on a silica gel (500 g) to give 6.5 g of the 2'-isomer and 3.5 g of the 3' isomer. The 2' -O-hexyl-Ω-N-phthalimido-5' -DMT-uridine (4 g, 5.2 mmole) was dissolved in 40 ML of anhydrous CH 2 C1 2 . To this solution diisopropylaminetetrazolide (0.5 g, 2.9 mmol) and bis (isopropylamino) -β-cyanoethoxyphosphine (2.5 mL, 7.0 mmol) were added and stirred overnight. TLC (1:1 EtoAC/hexane) showed complete disappearance of starring material. The reaction mixture was transferred with CH 2 C1 2 and washed with saturated NaHC0 3 (100 ML) followed by saturated NaCl solution. The organic layer was dried over anhydrous Na 2 S0 4 and evaporated to yield 6.4 g of a crude product which was purified in a silica column (200 g) using 1:1 hexane EtOAc to give 4.6 g (4.7 mmol, 90%) of the desired phosphoramidite. Example 21 Oligomer Synthesis and NMR characterization of an oligonucleotide containing U-2' -O-hexylamine linker An oligonucleotide of the sequence: Oligomer 22 TU*T where U* represents the hexylamine modified uridine moiety, was synthesized on a 10 mmol synthesis in the DNA synthesizer. The phosphoramidite from Example 20 was used as a 0.12 M solution in CH 3 CN. After deprotection of the oligonucleotide it was purified in a reverse phase HPLC column to get the pure trimer (any oligonucleotide containing undeprotected phthalimido group was separated from the trimer) . The oligonucleotide was dried, desalted and dissolved in 600 uL D 2 0 (app. 50 O.D., A 260 ) . Both the proton NMR and 31 P NMR were examined. ** Η NMR: 1.0-1.8 (m, CH2 protons from the hexyl chain) ; 5.75 (d) ; 5.9(d) ; 6.1 (t) ; 6.15 (t) ; 7.5 (s) . 31 p NMR: -0.2; -0.4 ppm (two lines) . Example 22 Synthesis illustrating preparation of any nucleotide (A, U, C or- G) placed opposite to an abasic site in an opposing strand A. Oligonucleotide Synthesis An oligonucleotide of the sequence: Oligomer 23 GGC TGU* CTG CG (P=0) wherein U* indicates a 2' -O- (hexylamino) uridine nucleotide was prepared using an extended coupling time of 10 minutes. 5'-Di- methyoxytrityl-2 ' -0- (hexyl-N-phthalimido) uridine phosphoramidite was used as a 0.12M solution in anhydrous CH3CN. The oligonucleotide was deprotected, purified in reverse phase HPLC (trityl-on) , deprotected at the 5'-position and purified again to remove any undeprotected phthalimido oligonucleotide. B. Cross linking reaction The Oligomer 23 oligonucleotide was reacted with the abasic oligonucleotide CGC AGD* CAG CC (Oligomer 2) with a crosslinking efficient of >90%. The formation of the conjugate was confirmed by reverse phase HPLC, ion-exchange HPLC and finally by the observation of base paired crosslinked duplex imino protons in the NMR spectrum. Example 23 Formation of a crosslink between a chimeric oligonucleotide and an abasic site containing oligonucleotide. An oligonucleotide of the sequence: Oligomer 24 G S G S C 0 T 0 G 0 U* 0 C 0 T 0 G S C S G where s represents a phosphorothioate backbone, o represents a phosphodiester backbone and U* represents a 2' -O- (hexylamino) uridine, was synthesized with a mixed (phosphodiester/phos- phorothioate) backbone using either a conventional iodine oxidation (P=0) or a Beaucage reagent oxidation (P=S) in the respective oxidation steps. The oligonucleotide was synthesized, purified and crosslinked with CGCAGD*CAGCC. The crosslinked duplex was characterized by 1 H NMR, Gel analysis, HPLC (reverse phase and ion-exchange) . Example 24 Cross linked nucleic acid duplex involving connectivity between two abasic sites: Oligonucleotides with the following sequences were synthesized: Oligomer 2 CGC AGD* CAG CC Oligomer 26 GGC TGD* CTG CG. Oligomer 26 was obtained from a precursor oligomer: Oligomer 25 GGC TGU CTG CG where U represents 2' -deoxyuridine, by the action of uracil-DNA glycosylase. Oligomer 2 is reacted with 1,6-hexanediamine in NaOAc/NaCNBH 3 medium and a product isolated that has a free amino group located on the linker. This modified oligonucleotide is mixed with oligomer 26 in NaOAc buffer followed by the addition of NaCNBH3 in NaOAC buffer. The resultant cross link has a connectivity between two abasic sites separated by the -NH- (CH 2 ) 6 -NH-linker. where "|" represents a -CH2-NH- (CH 2 ) 6 -NH-CH2-crosslinker. Example 25 T m determination of the Cross-linked Strands I. The melting behavior of the crosslinked duplex, Cross- linked Strand I, was determined at lOOmM Nacl, lOmM sodium phosphate, 0.1 mM EDTA at pH 7.0 at 4mM each strand concentration. Oligomer 5 - Oligomer 1 duplex (wild type) 48°C Oligomer 5 - Oligomer 2 duplex (abasic site) <30°C Oligomer 5 - Oligomer 2 Cross-linked Strands I 74°C The higher T m of the crosslinked duplex confirmed the covalent linkage between the two strands (Oligomer 5 and Oligomer 2) . EVALUATION PROCEDURE 1 - Nuclease Resistance A. Evaluation of the resistance of cross-linked oligonucleotides to serum and cytoplasmic nucleases. Cross-linked oligonucleotides of the invention can be assessed for their resistance to serum nucleases by incubation of the cross-linked oligonucleotide in media containing various concentrations of fetal calf serum or adult human serum. Labeled cross-linked oligonucleotides are incubated for various times, treated with protease K and then analyzed by gel electrophoresis on 20% polyacrylamine-urea denaturing gels and subsequent autoradiography. Autoradiograms are quantitated by laser densitometry. Based upon the location of the modified linkage and the known length of the cross-linked oligonucleotide it is possible to determine the effect on nuclease degradation by the particular modification. For the cytoplasmic nucleases, an HL-60 cell line can be used. A post-mitochondrial supernatant is prepared by differential centrifugation and the labelled cross-linked oligonucleotides are incubated in this supernatant for various times. Following the incubation, the cross-linked oligonucleotides are assessed for degradation as outlined above for serum nucleolytic degradation. Autoradiography results are quantitated for comparison of the unmodified and the cross-linked oligonucleotides of the invention. It is expected that the cross-linked oligonucleotides will be completely resistant to serum and cytoplasmic nucleases. B. Evaluation of the resistance of cross-linked oligonucleotides to specific endo- and exo-nucleases Evaluation of the resistance of natural oligonucleo¬ tides and cross-linked oligonucleotides of the invention to specific nucleases (i.e., endonucleases, 3',5'-exo-, and 5' ,3' -exonucleases) can be done to determine the exact effect of the modified linkage on degradation. The cross-linked oligonucleotides are incubated in defined reaction buffers specific for various selected nucleases. Following treatment of the products with protease K, urea is added and analysis on 20% polyacrylamide gels containing urea is done. Gel products are visualized by staining with Stains All reagent (Sigma Chemical Co.). Laser densitometry is used to quantitate the extent of degradation. The effects of the modified linkage are determined for specific nucleases and compared with the results obtained from the serum and cytoplasmic systems. As with the serum and cytoplasmic nucleases, it is expected that the cross¬ linked oligonucleotides of the invention will be completely resistant to endo- and exo-nucleases. PROCEDURE 2 - 5-Lipoxygenase Analysis and Assays A. . Therapeutics For therapeutic use, an animal suspected of having a disease characterized by excessive or abnormal supply of 5-lipoxygenase is treated by administering cross-linked oligonucleotides in accordance with this invention. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Such treatment is generally continued until either a cure is effected or a diminution in the diseased state is achieved. Long term treatment is likely for some diseases. B. Research Reagents The cross-linked oligonucleotides of this invention will also be useful as research reagents when used to cleave or otherwise modulate 5-lipoxygenase mRNA in crude cell lysates or in partially, purified or wholly purified RNA preparations. This application of the invention is accomplished, for example, by lysing cells by standard methods, optimally extracting the RNA and then treating it with a composition at concentrations ranging, for instance, from about 100 to about 500 ng per 10 μg of total RNA in a buffer consisting, for example, of 50 mm phosphate, pH ranging from about 4-10 at a temperature from about 30° to about 50° C. The cleaved 5-lipoxygenase RNA can be analyzed by agarose gel electrophoresis and hybridization with radiolabeled DNA probes or by other standard methods. C. Diagnostics The cross-linked oligonucleotides of this invention will also be useful in diagnostic applications, particularly for the determination of the expression of specific mRNA species in various tissues or the expression of abnormal or mutant RNA species. In this example, the cross-linked oligonucleotides target a hypothetical abnormal mRNA by being designed complementary to the abnormal sequence, but would not hybridize to normal mRNA. Tissue samples can be homogenized, and RNA extracted by standard methods. The crude homogenate or extract can be treated for example to effect cleavage of the target RNA. The product can then be hybridized to a solid support which contains a bound oligonucleotide complementary to a region on the 5' side of the cleavage site. Both the normal and abnormal 5' region of the mRNA would bind to the solid support. The 3' region of the abnormal RNA, which is cleaved, would not be bound to the support and therefore would be separated from the normal mRNA. Targeted mRNA species for modulation relates to 5- lipoxygenase; however, persons of ordinary skill in the art will appreciate that the present invention is not so limited and it is generally applicable. The inhibition or modulation of production of the enzyme 5-lipoxygenase is expected to have significant therapeutic benefits in the treatment of disease. In order to assess the effectiveness of the compositions, an assay or series of assays is required. D. In Vitro Assays The cellular assays for 5-lipoxygenase preferably use the human promyelocytic leukemia cell line HL-60. These cells can be induced to differentiate into either a monocyte-like cell or neutrophil-like cell by various known agents. Treatment of the cells with 1.3% dimethyl sulfoxide, DMSO, is known to promote differentiation of the cells into neutrophils. It has now been found that basal HL-60 cells do not synthesize detectable levels of 5-lipoxygenase protein or secrete leukotrienes (downstream products of 5-lipoxygenase) . Differentiation of the cells with DMSO causes an appearance of 5-lipoxygenase protein and leukotriene biosynthesis 48 hours after addition of DMSO. Thus induction of 5-lipoxygenase protein synthesis can be utilized as a test system for analysis of cross-linked oligonucleotides which interfere with 5- lipoxygenase synthesis in these cells. A second test system for cross-linked oligonucleotides makes use of the fact that 5-lipoxygenase is a "suicide" enzyme in that it inactivates itself upon reacting with substrate. Treatment of differentiated HL-60 or other cells expressing 5- lipoxygenase, with 10 μM A23187, a calcium ionophore, promotes translocation of 5-lipoxygenase from the cytosol to the membrane with subsequent activation of the enzyme. Following activation and several rounds of catalysis, the enzyme becomes catalytically inactive. Thus, treatment of the cells with calcium ionophore inactivates endogenous 5-lipoxygenase. It takes the cells approximately 24 hours to recover from A23187 treatment as measured by their ability to synthesize leukotriene B 4 . Cross-linked oligonucleotides directed against 5-lipoxygenase can be tested for activity in two HL-60 model systems using the following quantitative assays. * The assays are described from the most direct measurement of inhibition of 5-lipoxygenase protein synthesis in intact cells to more downstream events such as measurement of 5-lipoxygenase activity in intact cells. The most direct effect which cross-linked oligonuc¬ leotides can exert on intact cells and which can be easil quantitated is specific inhibition of 5-lipoxygenase protei synthesis. To perform this technique, cells can be labelle with 35 S-methionine (50 μCi/mL) for 2 hours at 37° C to labe newly synthesized protein. Cells are extracted to solubiliz total cellular proteins and 5-lipoxygenase i immunoprecipitated with 5-lipoxygenase antibody followed b elution from protein A-Sepharose beads. The immunoprecipitate proteins are resolved by SDS-polyacrylamide gel electrophoresi and exposed for autoradiography. The amount o immunoprecipitated 5-lipoxygenase is quantitated by scanning densitometry. A predicted result from these experiments would be as follows. The amount of 5-lipoxygenase protein immuno- precipitated from control cells would be normalized to 100%. Treatment of the cells with 1 μM, 10 μM, and 30 μM of effective cross-linked oligonucleotides for 48 hours would reduce immunoprecipitated 5-lipoxygenase by 5%, 25% and 75% of control, respectively. Measurement of 5-lipoxygenase enzyme activity in cellular homogenates could also be used to quantitate the amount of enzyme present which is capable of synthesizing leukotrienes. A radiometric assay has now been developed for quantitating 5-lipoxygenase enzyme activity in cell homogenates using reverse phase HPLC. Cells are broken by sonication in a buffer containing protease inhibitors and. EDTA. The cell homogenate is centrifuged at 10,000 x g for 30 min and the supematants analyzed for 5-lipoxygenase activity. Cytosolic proteins are incubated with 10 μM 14 C-arachidonic acid, 2mM ATP, 50 μM free calcium, 100 μg/ml phosphatidylcholine, and 50 mM bis-Tris buffer, pH 7.0, for 5 min at 37° C. The reactions are quenched by the addition of an equal volume of acetone, and the fatty acids extracted with ethyl acetate. The substrate and reaction products are separated by reverse phase HPLC on a Novapak C18 column (Waters Inc., Millford, MA) . Radioactive peaks are detected by a Beckman model 171 radiochromatography detector. The amount of arachidonic acid converted into di- HETE's and mono-HETE's is used as a measure of 5-lipoxygenase activity. A predicted result for treatment of DMSO differ¬ entiated HL-60 cells for 72 hours with effective cross-linked oligonucleotides at 1 μM, 10 μM, and 30 μM would be as follows. Control cells oxidize 200 pmol arachidonic acid/ 5 min/ 10 6 cells.- Cells treated with 1 μM, 10 μM, and 30 μM of an effective cross-linked oligonucleotides would oxidize 195 pmol, 140 pmol, and 60 pmol of arachidonic acid/ 5 min/ 10 6 cells respectively. A quantitative competitive enzyme linked immunosorbant assay (ELISA) for the measurement of total 5-lipoxygenase protein in cells has been developed. Human 5-lipoxygenase expressed in E. coli and purified by extraction, Q-Sepharose, hydroxyapatite, and reverse phase HPLC is used as a standard and as the primary antigen to coat microtiter plates. 25 ng of purified 5-lipoxygenase is bound to the microtiter plates overnight at 4° C. The wells are blocked for 90 min with 5% goat serum diluted in 20 mM Tris-HCL buffer, pH 7.4, in the presence of 150 mM NaCl (TBS) . Cell extracts (0.2% Triton X- 100, 12,000 x g for 30 min.) or purified 5-lipoxygenase were incubated with a 1:4000 dilution of 5-lipoxygenase polyclonal antibody in a total volume of 100 μL in the microtiter wells for 90 min. The antibodies are prepared by immunizing rabbits with purified human recombinant 5-lipoxygenase. The wells are washed with TBS containing 0.05% Tween 20 (TBST) , then incubated with 100 μL of a 1:1000 dilution of peroxidase conjugated goat anti-rabbit IgG (Cappel Laboratories, Malvern, PA) for 60 min at 25° C. The wells are washed with TBST and the amount of peroxidase labelled second antibody determined by development with tetramethylbenzidine. Predicted results from such an assay using a 30-mer cross-linked oligonucleotide at 1 μM, 10 μM, and 30 μM would be 30 ng, 18 ng and 5 ng of 5-lipoxygenase per 10 6 cells, respectively, with untreated cells containing about 34 ng 5- lipoxygenase. A net effect of inhibition of 5-lipoxygenase biosyn¬ thesis is a diminution in the quantities of leukotrienes released from stimulated cells. DMSO-differentiated HL-60 cells release leukotriene B4 (LTB4) upon stimulation with the calcium ionophore A23187. Leukotriene B4 released into the cell medium can be quantitated by radioimmunoassay using commercially available diagnostic kits (New England Nuclear, Boston, MA) . Leukotriene B4 production can be detected in HL- 60 cells 48 hours following addition of DMSO to differentiate the cells into neutrophil-like cells. Cells (2 x 10 5 cells/mL) will be treated with increasing concentrations of cross-linked oligonucleotides for 48-72 hours in the presence of 1.3 % DMSO. The cells are washed and resuspended at a concentration of 2 x 10 6 cell/mL in Dulbecco's phosphate buffered saline containing 1% delipidated bovine serum albumin. Cells are stimulated with 10 μM calcium ionophore A23187 for 15 min and the quantity of LTB4 produced from 5 x 10 5 cells determined by radioimmunoassay as described by the manufacturer. Using this assay the following results would likely be obtained with a cross-linked oligonucleotide directed to the 5-lipoxygenase mRNA. Cells will be treated for 72 hours with either 1 μM, 10 μM or 30 μM cross-linked oligonucleotide in the presence of 1.3% DMSO. The quantity of LTB 4 produced from 5 x 10 5 cells would be expected to be about 75 pg, 50 pg, and 35 pg, respectively with untreated differentiated cells producing 75 pg LTB 4 . E. In Vivo Assay Inhibition of the production of 5-lipoxygenase in the mouse can be demonstrated in accordance with the following protocol. Topical application of arachidonic acid results in the rapid production of leukotriene B 4 , leukotriene C 4 and prostaglandin E 2 in the skin followed by edema and cellular infiltration. Certain inhibitors of 5-lipoxygenase have been known to exhibit activity in this assay. For the assay, 2 mg of arachidonic acid is applied to a mouse ear with the contralateral ear serving as a control. The polymorphonuclear cell infiltrate is assayed by myeloperoxidase activity in homogenates taken from a biopsy 1 hour following the administration of arachidonic acid. The edematous response is quantitated by measurement of ear thickness and wet weight of a punch biopsy. Measurement of leukotriene B 4 produced in biopsy specimens is performed as a direct measurement of 5- lipoxygenase activity in the tissue. Cross-linked oligonucleotides will be applied topically to both ears 12 to 24 hours prior to administration of arachidonic acid to allow optimal activity of the compounds. Both ears are pretreated for 24 hours with either 0.1 μmol, 0.3 μmol, or 1.0 μmol of the oligonucleotide prior to challenge with arachidonic acid. Values are expressed as the mean for three animals per concentration. Inhibition of polymorphonuclear cell infiltration for 0.1 μmol, 0.3 μmol, and 1 μmol is expected to be about 10 %, 75 % and 92 % of control activity, respectively. Inhibition of edema is expected to be about 3%, 58% and 90%, respectively while inhibition of leukotriene B 4 production would be expected to be about 15%, 79% and 99%, respectively. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: David Ecker (ii) TITLE OF INVENTION: Covalently Cross-Linke Oligonucleotides (iii) NUMBER OF SEQUENCES: 24 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Woodcock Washburn Kurtz Mackiewicz & Norris (B) STREET: One Liberty Place - 46th Floor (C) CITY: Philadelphia (D) STATE: PA (E) COUNTRY : USA (F) ZIP: 19103 (v) COMPUTER READABLE FORM: - (A) MEDIUM TYPE: DISKETTE, 3.5 INCH, 1.44 Mb STORAGE (B) COMPUTER: IBM PS/2 (C) OPERATING SYSTEM: PC-DOS (D) SOFTWARE: WORDPERFECT 5.1 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: n/a (B) FILING DATE: Herewith (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: 846,376 -(B) FILING DATE: March 5, 1992 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Joseph Lucci (B) REGISTRATION NUMBER: 33,307 (C) REFERENCE/DOCKET NUMBER: ISIS-0980 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (215) 568-3100 (B) TELEFAX: (215) 568-3439 (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: CGCAGUCAGC C 11 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: CGCAGDCAGC C 11 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: ' (A) LENGTH: 20 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: GACAGAGGUA GGAGAAGUGA 20 (2) INFORMATION FOR SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: GACAGAGGDA GGAGAAGDGA 20 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: GGCTGACTGC G 11 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 ' (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear ( iv) ANTI -SENSE : yes (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: CTGTCTCCAT CCTCTTCACT 20 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: GGCTGACTGC G 11 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: GGCTGACTGC G 11 (2) INFORMATION FOR SEQ ID NO: 9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid ' (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9: GGCTGACTGC G 11 (2) INFORMATION FOR SEQ ID NO: 10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: GGCTGUCTGC G 11 (2) INFORMATION FOR SEQ ID NO: 11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: AGCCAGAUCU GAGCCUGGGA GCUCUCUGGC U 31 (2) INFORMATION FOR SEQ ID NO: 12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single " (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12: GGCTGUCTGC G 11 (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: GGCTGUCTGC G 11 (2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: GGCTGUCTGC G 11 (2) INFORMATION FOR SEQ ID NO: 15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15: GGCTGUCTGC G 11 (2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: AGCCAGAUCU GAGCCUGGGA GCUCUCUGGC U 31 (2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: AGCCAGAUCU GAGCCUGGGA GCUCUCUGGC U 31 (2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 19 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) ' SEQUENCE DESCRIPTION: SEQ ID NO: 18: GACAGAGGUA GGAGAAUGA 19 (2) INFORMATION FOR SEQ ID NO: 19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: AGCCAGAUCU GAGCCUGGGA GCUCUCUGGC U 31 (2) INFORMATION FOR SEQ ID NO: 20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20: AGCCAGAUCU GAGCCUGGGA GCUCUCUGGC U 31 (2) INFORMATION FOR SEQ ID NO: 21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21: GGCTGUCTGC G 11 (2) INFORMATION FOR SEQ ID NO: 22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH : 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22: GGCTGUCTGC G 11 (2) INFORMATION FOR SEQ ID NO: 23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23: GGCTGDCTGC G 11 (2) INFORMATION FOR SEQ ID NO: 24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 (B) TYPE, nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iv) ANTI-SENSE: no (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: GGCTGUCTGC G 11

Claims: WHAT IS CLAIMED IS: 1. A cross-linked nucleic acid comprising: a first nucleotide located on a first oligonucleo¬ tide strand; a first bond means located on a sugar moiety of said first nucleotide; a second nucleotide located on a further oligonucleotide strand; a second bond means located on a sugar moiety of said second nucleotide; and a covalent cross-linkage between said first and said second bond means. 2. A cross-linked nucleic acid comprising: a first nucleotide located on an oligonucleotide strand; a first bond means located on a sugar moiety of said first nucleotide; a second nucleotide located on said oligonucleotide strand; a second bond means located on a sugar moiety of said second nucleotide; and a covalent cross-linkage between said first and said second bond means. 3. A cross-linked nucleic acid comprising: a first nucleotide located on a 3' end of a first oligonucleotide strand, said first nucleotide including a 2' ,3' -dialdehyde structure; a second nucleotide located on a further oligonucleotide strand or on said first oligonucleotide strand; a space-spanning group located on a sugar moiety of said second nucleotide; an active functional group located on said space- spanning group; and a covalent cross-linkage between said dialdehyde structure and said active functional group. 4. A cross-linked nucleic acid comprising: a first nucleotide located on a 3' end of a first oligonucleotide strand, said first nucleotide including 2' and 3' hydroxyl groups; a second nucleotide located on a further oligonucleotide strand or on said first oligonucleotide strand; a space-spanning group located on a sugar moiety of said second specific nucleotide; an active functional group located on said space- spanning group; and a covalent acetal cross-linkage between said 2' and 3' hydroxyl groups and said active functional group. 5. A cross-linked nucleic acid comprising: a first nucleotide located on a first oligonucleotide strand; a first bond means located on a sugar moiety of said first nucleotide; a second nucleotide located on a further oligonucleotide strand or on said first oligonucleotide strand; a second bond means located on said second nucleotide; and a covalent cross-linkage between said first and said second bond means. 6. The cross-linked nucleic acid of claim 5 wherein: said first nucleotide is located in a first nucleotide sequence and said second nucleotide is located in a second nucleotide sequence; said second nucleotide sequence is complementary to and hybridizable with said first nucleotide sequence; and said first and said second nucleotide sequences are located on a single strand of said oligonucleotide with said second nucleotide sequence located on said oligonucleotide at a distance separated from said first nucleotide sequence sufficient to allow said oligonucleotide to assume a conformation wherein said first and second nucleotide sequences are mutually aligned with and specifically hybrid¬ ized with one another. 7. The cross-linked nucleic acid of claim 5 wherein: said first nucleotide is located in a first nucleotide sequence and said second nucleotide is located in a second nucleotide sequence; said second nucleotide sequence is complementary to and specifically hybridizable with said first nucleotide sequence; and said first and said second nucleotide sequences are located on different oligonucleotide strands. 8. The cross-linked nucleic acid of' claim 5 wherein: said first bond means includes an abasic site; said second bond means includes a space-spanning group having an active functional group, and said .active functional group is covalently bonded with said abasic site. 9. The cross-linked nucleic acid of claim 8 wherein: said abasic site includes an aldehyde; and said active functional group is capable of reacting with said aldehyde. 10. The cross-linked nucleic acid of claim 8 wherein said active functional group is an amine, hydrazine, hydroxylamine, semicarbazide, thiosemicarbazide, hydrazone, hydrazide, alcohol or thiol . 11. The cross-linked nucleic acid of claim 10 wherein said active functional group is an amine . 12. The cross-linked nucleic acid of claim 8 wherein said space -spanning group is attached to a 2 ' -position of said second nucleotide . 13 . The cross-linked nucleic acid of claim 8 wherein said space- spanning group is ^C^ straight chain alkyl, C-^C^ straight chain 0-alkyl, C 1 -C 20 straight chain S- alkyl, C 1 -C 20 straight chain NH-alkyl, C 1 -C 20 straight chain substituted alkyl, C- . -C 20 straight chain substituted 0-alkyl, C^C ao straight chain substituted S-alkyl, C x -C 20 straight chain substituted NH-alkyl , C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain O-alkyl, C 2 -C 50 branched chain S- alkyl, C 2 -C 50 branched chain NH-alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 50 branched chain substituted 0-alkyl, C 2 -C 50 branched chain substituted S-alkyl, C 2 -C 50 branched chain substituted NH-alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain O-alkenyl, C 2 -C 20 straight chain S-alkenyl , C 2 - C 20 straight chain NH-alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 2 -C 20 straight chain substituted O-alkenyl, C 2 -C 20 straight chain substituted S-alkenyl, C 2 -C 20 straight chain substituted NH-alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain O-alkenyl , C 3 -C 50 branched chain S-alkenyl , C 3 - C 50 branched chain NH-alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 3 -C 50 branched chain substituted O-alkenyl , C 3 -C 50 branched chain substituted S-alkenyl, C 3 -C 50 branched chain substituted NH-alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain 0-alkyne, C 2 -C 20 straight chain S-alkyne, C 2 -C 20 straight chain NH-alkyne, C 2 -C 20 straight chain substituted alkyne, C 2 -C 20 straight chain substituted O-alkyne, C 2 -C 20 straight chain substituted S-alkyne, C 2 -C 20 straight chain substituted NH-alkyne, C 3 -C 50 branched chain alkyne, C 2 -C 50 branched chain 0-alkyne, C 3 -C 50 branched chain S-alkyne, C 3 -C 50 branched chain NH-alkyne, C 3 -C 50 branched chain substituted alkyne, C 3 -C 50 branched chain substituted O-alkyne, C 3 -C 50 branched chain substituted S-alkyne, C 3 -C 50 branched chain substituted NH-alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic. 14. The cross-linked nucleic acid of claim 13 wherein said space-spanning group is from about 8 to about 13 atoms in length. 15. The cross-linked nucleic acid of claim 5 wherein: said first bond means includes a first space- spanning group having a first active functional group; said second bond means includes a second space- spanning group having a second active functional group; and said covalent cross-linkage is between said first and said second active functional groups. 16. The cross-linked nucleic acid of claim 15 wherein said first active functional group is an aldehyde, a protected aldehyde or an aldehyde precursor. 17. The cross-linked nucleic acid of claim 16 wherein said first active functional group is C-formyl, o-methylaminobenzenethiol, aryl substituted imidazolidino, dithiane, bis (p-nitrophenoxy) , acetal, nitrile, ester or alcohol. 18. The cross-linked nucleic acid of claim 15 wherein said second active functional group is an art ne, hydrazine, hydroxylamine, semicarbazide, thiosemicarba£ * de, hydrazide, alcohol or thiol. 19 . The cross-linked nucleic acid of claim 15 wherein : said first space -spanning group is attached to a 2 ' - position of said first nucleotide; and said second space- spanning group is attached to a 2 ' -position of said second nucleotide . 20. The cross-linked nucleic acid of claim 15 wherein each of said first and second space- spanning groups are, independently, C 1 -C 20 straight chain alkyl , C- L -C- Q straight chain O-alkyl, C 1 -C 20 straight chain S-alkyl , C 1 -C 20 straight chain NH-alkyl, C- . -C 20 straight chain substituted alkyl , C- . -C 20 straight chain substituted 0-alkyl, C^ ^ straight chain substituted S-alkyl , C x -C 20 straight chain substituted NH- alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain O- alkyl , C 2 -C 50 branched chain S-alkyl, C 2 -C 50 branched chain NH- alkyl, C 2 -C 50 branched chain substituted alkyl , C 2 -C 50 branched chain substituted O-alkyl , C 2 -C 50 branched chain substituted S-alkyl , C 2 -C 50 branched chain substituted NH-alkyl , C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain O-alkenyl, C 2 -C 20 straight chain S-alkenyl, C 2 -C 20 straight chain NH-alkenyl , C 2 - C 20 straight chain substituted alkenyl, C 2 -C 20 straight chain substituted O-alkenyl, C 2 -C 20 straight chain substituted S-alkenyl, C 2 -C 20 straight chain substituted NH-alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain O-alkenyl , C 3 -C 50 branched chain S-alkenyl, C 3 -C 50 branched chain NH-alkenyl , C 3 - C 50 branched chain substituted alkenyl, C 3 -C 50 branched chain substituted O-alkenyl, C 3 -C 50 branched chain substituted S- alkenyl , C 3 -C 50 branched chain substituted NH-alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain 0-alkyne, C 2 -C 20 straight chain S-alkyne, C 2 -C 20 straight chain NH-alkyne, C 2 -C 20 straight chain substituted alkyne, C 2 -C 20 straight chain substituted O-alkyne, C 2 -C 20 straight chain substituted S- alkyne,. C 2 -C 20 straight chain substituted NH-alkyne, C 3 -C 50 branched chain alkyne, C 2 -C 50 branched chain O-alkyne, C 3 -C S0 branched chain S-alkyne, C 3 -C 50 branched chain NH-alkyne , C 3 -C 50 branched chain substituted alkyne, C 3 -C 50 branched chain sub- stituted O-alkyne, C 3 -C 50 branched chain substituted S-alkyne, C 3 -C 50 branched chain substituted NH-alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic. 21. The cross-linked nucleic acid of claim 15 wherein said first and second active functional groups are thiol groups and said covalent cross-linkage is a disulfide bond. 22. The cross-linked nucleic acid of claim 5 wherein: said first nucleotide is located in a first nucleotide sequence and said second nucleotide is located in a second nucleotide sequence; and said first and said second nucleotide sequences are located on a single strand of an oligonucleotide with said second nucleotide sequence located on said oligonucleotide at a non-hybridizable position with respect to said first nucleotide sequence and at a distance from said first nucleotide sequence sufficient to allow said oligonucleotide to assume a conformation wherein said first and second nucleotide sequences are located in spatial proximity with each other. 23. The cross-linked nucleic acid of claim 5 wherein: said first bond means includes a 3'-terminal nucleoside having a 2' ,3' -dialdehyde structure; said second bond means includes an active functional group located on a space-spanning group; and said active functional group is capable of reacting with a dialdehyde. 24. The cross-linked nucleic acid of claim 5 wherein: said first bond means includes a 3' -terminal nucleotide having 2' and 3'-sugar hydroxyl groups; said second bond means includes an active functional group located on a space-spanning group; and an acetal cross-linkage connects said 2' and 3' hydroxyl groups and said active functional group. 25. A cross-linked oligonucleotide comprising: a first sequence region in an oligonucleotide,- a second sequence region in an oligonucleotide; an abasic site located in said first sequence region; a space-spanning group located on said second sequence region; and an active functional group located on said space- spanning group, wherein said active functional group is covalently bonded with said abasic site. 26. The cross-linked oligonucleotide of claim 25 wherein said first sequence region and said second sequence region are on a single oligonucleotide strand. 27. The cross-linked oligonucleotide of claim 25 wherein said first sequence region and said second sequence region are on different oligonucleotide strands. 28. The cross-linked oligonucleotide of claim 25 wherein said first sequence region and said second sequence region are complementary to and specifically hybridizable with one another. 29. The cross-linked oligonucleotide of claim 25 wherein said space-spanning group is C-_-C 20 straight chain alkyl, C- . -C-, 0 straight chain O-alkyl, C 1 -C 2Q straight chain S- alkyl, straight chain NH-alkyl, C 1 -C 20 straight chain substituted alkyl, C^C^ straight chain substituted O-alkyl, c ι -c 20 straight chain substituted S-alkyl, C 1 -C 20 straight chain substituted NH-alkyl, C 2 -C S0 branched chain alkyl, C 2 -C 50 branched chain O-alkyl, C 2 -C 50 branched chain S-alkyl, C 2 -C 50 branched chain NH-alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 50 branched chain substituted O-alkyl, C 2 -C 50 branched chain substituted S-alkyl, C 2 -C 50 branched chain substituted NH-alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain O-alkenyl, C 2 -C 20 straight chain S-alkenyl, C 2 - C 20 straight chain NH-alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 2 -C 20 straight chain substituted O-alkenyl, C 2 -C 20 straight chain substituted S-alkenyl, C 2 -C 20 straight chain substituted NH-alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain O-alkenyl, C 3 -C 50 branched chain S-alkenyl, C 3 - C 50 branched chain NH-alkenyl, C 3 -C S0 branched chain substituted alkenyl, C 3 -C 50 branched chain substituted O-alkenyl, C 3 -C 50 branched chain substituted S-alkenyl, C 3 -C 50 branched chain substituted NH-alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain O-alkyne, C 2 -C 20 straight chain S-alkyne, C 2 -C 20 straight chain NH-alkyne, C 2 -C 20 straight chain substituted alkyne, C 2 -C 20 straight chain substituted O-alkyne, C 2 -C 20 straight chain substituted S-alkyne, C 2 -C 20 straight chain substituted NH-alkyne, C 3 -C 50 branched chain alkyne, C 2 -C 50 branched chain O-alkyne, C 3 -C 50 branched chain S-alkyne, C 3 -C 50 branched chain NH-alkyne, C 3 -C 50 branched chain substituted alkyne, C 3 -C 50 branched chain substituted O-alkyne, C 3 -C 50 branched chain substituted S-alkyne, C 3 -C 50 branched chain substituted NH-alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic. 30. The cross-linked oligonucleotide of claim 25 wherein said active functional group is an amine, hydrazine, hydroxylamine, semicarbazide, hydrazide, alcohol or thiol. 31. The cross-linked oligonucleotide of claim 25 wherein said space -spanning group is CH 2 -L 3 , 0-L 3 , S-L 3 , NH-L 3 or CO-L 3 where L 3 is C 1 -C 20 straight chain alkyl, C x -C 20 straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic. 32. The cross-linked oligonucleotide of claim 25 wherein said space-spanning group is located on a 2'-position of a nucleotide within said second sequence region. 33. A cross-linked oligonucleotide comprising: a first sequence region in an oligonucleotide; a second sequence region in an oligonucleotide; and a covalently bonded linker of the structure: wherein X x is covalently connected to said first sequence re¬ gion, X 2 is covalently connected to said second sequence region, and where: (i) X- L and X 2 , independently, are O, S, NH, CH 2 or CO; L- L and L 2 , independently, are C- L -C^ straight chain alkyl, C- L -C^ straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, polyether, aryl, aralkyl or heterocyclic; and Y is an imine, amine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide-hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal, thiohemiacetal, α-keto-alkylthioalkyl or of-keto-alkylaminoalkyl; or (ii) X x and X 2 , independently, are O or NH; and i-Y-La together are NH-L 3 -NH or NH-NH-L 3 -NH-NH; and L 3 is C 1 -C 20 straight chain alkyl, C 1 -C 20 straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 - C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene ■ glycol, polyether, aryl, aralkyl or heterocyclic; or (iii) X- L and X 2 , independently, are O, S, NH, CH 2 or CO; L- . and L 2 , independently, are C- L -C^ straight chain alkylamino, C- L -C,,- straight chain substituted alkylamino, C : -C 50 branched chain alkylamino, C 2 -C 50 branched cha ~ ". substituted alkylamino, C 2 -C 20 straight chai. alkenylamino, C 2 -C 20 straight chain substituted ε....-ienylamino, C 3 -C 50 branched chain alkenylamino, - 3 -C 50 branched chain substituted alkenylamino, ~ - . -C 20 straight chain alkynylamino, C 2 - C 20 straight »..'in substituted alkynylamino, C 3 -C 30 . branched chai alkynylamino, C 3 -C 50 branched chain substituted έ.ikynylamino, C- ^ -C^ straight chain alkylthio, C 1 -C 20 straight chain substituted alkylthio, C 2 -C 50 branched chain alkylthio, C 2 -C 50ι branched chain substituted alkylthio, C 2 -C 20 straight chain alkenylthio, C 2 -C 20 straight chain substituted alkenylthio, C 3 -C 50 branched chain alkenylthio, C 3 -C 50 branched chain substituted alkenylthio, C 2 -C 20 straight chain alkynylthio, C 2 -C 20 straight chain substituted alkynylthio, C 3 -C 50 branched chain alkynylthio or C 3 -C 50 branched chain substituted alkynylthio; and Y is a heterobifunctional or homobifunctional cross-linking reagent; where said substituent of said substituted alkyl, substituted alkenyl and substituted alkyne moieties is an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that enhances the pharmacodynamic properties of oligonucleotides or a group that enhances the pharmacokinetic properties of oligonucleotides. 34. The cross-linked oligonucleotide of claim 33 wherein: X x and X 2 , independently, are 0, S, NH, CH 2 or CO; L x and L 2 , independently, are C^C^ straight chain alkyl, C- L -C JO straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50/ branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic; and Y is imine, amine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide-hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarb- azone, .disulfide, hemiacetal, thiohemiacetal, α-keto-alkyl- thioalkyl or Qf-keto-alkylaminoalkyl. - Ill - 35. The cross-linked oligonucleotide of claim 34 wherein X and X 2 , independently, are 0, S or NH. 36. The cross-linked oligonucleotide of claim 34 wherein Y is imine, amine, oxime, hydrazine, hydrazone or hydroxylamine. 37. The cross-linked oligonucleotide of claim 34 wherein Y is disulfide. 38. The cross-linked oligonucleotide of claim 33 wherein; X x and X 2 , independently, are 0 or NH; together L 1 -Y-L 2 are HN-L 3 -NH; and L 3 is C 1 -C 20 straight chain alkyl, C- . -C 20 straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic. 39. The cross-linked oligonucleotide of claim 38 wherein X x and X 2 are 0. 40. The cross-linked oligonucleotide of claim 38 wherein L 3 is polymethylene. 41. The cross-linked oligonucleotide of claim 33 wherein said first sequence region and said second sequence region are on a single oligonucleotide strand. 42. The cross-linked oligonucleotide of claim 33 wherein said first sequence region and said second sequence region are on different oligonucleotide strands. 43. The cross-linked oligonucleotide of claim 33 wherein: X-_ and X 2 , independently, are 0, S, NH, CH 2 or CO; L x and L 2 , independently, are C 1 -C 20 straight chain alkylamino, C- L -C-Q straight chain substituted alkylamino, C 2 -C 50 branched chain alkylamino, C 2 -C 50 branched chain substituted alkylamino, C 2 -C 20 straight chain alkenylamino, C 2 -C 20 straight chain substituted alkenylamino, C 3 -C 50 branched chain alkenylamino, C 3 -C 50 branched chain substituted alkenylamino, C 2 -C 20 straight chain alkynylamino, C 2 -C 20 straight chain substituted alkynylamino, C 3 -C 50 branched chain alkynylamino, C 3 -C 50 branched chain substituted alkynylamino, C^ ^ straight chain alkylthio, C- . -C 20 straight chain substituted alkylthio, C 2 -C 5Q branched chain alkylthio, C 2 -C 50 branched chain substituted alkylthio, C 2 -C 20 straight chain alkenylthio, C 2 -C 20 straight chain substituted alkenylthio, C 3 -C 50 branched chain alkenylthio, C 3 -C 50 branched chain substituted alkenylthio, C 2 - C 20 straight chain alkynylthio, C 2 -C 20 straight chain substituted alkynylthio, C 3 -C 50 branched chain alkynylthio or C 3 -C 50 branched chain substituted alkynylthio; and Y is a heterobifunctional or homobifunctional cross- linking reagent. 44. The cross-linked oligonucleotide of claim 43 wherein Y is a heterobifunctional cross-linking reagent comprising two reactive moieties independently selected from maleimide, N-hydroxysuccinimide, N-hydroxysulfosuccinimide, imidoester, pyridyl disulfide, β-carbonyl alkylhalide or photoreactive aryl azide. 45. A cross-linked oligonucleotide comprising: a first sequence region in an oligonucleotide; a second sequence region in an oligonucleotide; a first space-spanning group connected to a 2'- position of a nucleotide located in said first sequence region; a second space-spanning group connected to a 2'- position of a nucleotide located on said second sequence region; and a linking moiety covalently bonding said first and second space-spanning groups. 46. The cross-linked oligonucleotide of claim 45 wherein: said linking moiety is -N=CH- , -N(R) -CH 2 -N(R) - , -N(R)-, -0-N=CH-, -O-N(R)-, -N(R)-N(R)-, -HC=N-N(R)-, -HC=N-N=CH-, -C(0) -N(R) -N=CH-, -C(0)N(R)-, -C(0) -N(R) -N(R) - , -N(R) -C (0) -N(R) -N(R) - , -N(R) -C(0) -N(R) -N=CH-, -N(R) -C(S)-N(R) -N(R) -, -N(R) -C(S) -N(R) -N=CH-, -S-S-, -CH(0H)-0-CH 2 -, -CH(0H)-S-CH 2 -, -CH 2 -S-CH 2 -C(0) -CH 2 - or -CH 2 -NH-CH 2 -C(0) -CH 2 -; and R is H, alkyl, alkenyl, aralkyl, an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that enhances the pharmacodynamic properties of oligonucleotides or a group that enhances the pharmacokinetic properties of oligonucleotides. 47. The cross-linked oligonucleotide of claim 46 wherein R is H. 48. A method of fixing an oligonucleotide in a set configuration comprising: selecting a first site in said oligonucleotide, said first site having a first nucleotide sequence; attaching a first bond precursor to the sugar moiety of a first nucleotide of said first site; selecting a second site in said oligonucleotide, said second site having a second nucleotide sequence; attaching a second bond precursor to the sugar moiety -of a second nucleotide of said second site; and forming a covalent cross-linkage between said first and said second bond precursors. 49. The method of claim 48 including: attaching said first bond precursor to said first nucleotide by reacting a precursor of said first nucleotide with a reagent for introducing said first bond precursor on the sugar moiety of said first nucleotide precursor; derivatizing said first nucleotide precursor to a protected and activated form; synthetically incorporating said derivatized first nucleotide precursor into said first nucleotide sequence; attaching said second bond precursor to said second nucleotide by reacting a precursor of said second nucleotide with a reagent for introducing said second bond precursor on the sugar moiety of said second nucleotide precursor; derivatizing said second nucleotide precursor to a protected and activated form; and synthetically incorporating said derivatized second nucleotide precursor into said second nucleotide sequence. 50. The method of claim 48 including: selecting an abasic nucleotide as said first bond precursor; and attaching said second bond precursor to a 2' - position of said second nucleotide. 51. The method of claim 48 including: attaching said first bond precursor to a 2 ' -position of said first nucleotide; and attaching said second bond precursor to a 2' - position of said second nucleotide. 52. The method of claim 51 including selecting said cross-1inkage from: -N=CH-, -N(R)-, -N(R) -CH 2 -NH-, -NH-CH 2 -NH-, -0-N=CH-, -O-N(R) -, -N(R) -N(R) -, -HC=N-N(R) -, -HC=N-N=CH-, -C(O) -N(R) -N=CH-, -C(0)N(R)-, -C(O)- N(R)-N(R)-, -N(R) -C(0)-N(R)-N(R) -, -N(R) -C(O) -N(R) -N=CH-, -N(R) -C(S) -N(R) -NH-, -N(R) -C(S) -N(R) -N=CH-, -S-S-, -CH(OH) -0-CH 2 -, -CH(OH) -S-CH 2 -, -CH 2 -S-CH 2 - C(0)-CH 2 - or -CH 2 -NH-CH 2 -C(0) -CH 2 -; wherein R is H, alkyl, alkenyl, aralkyl, an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that enhances the pharmacodynamic properties of cross-linked duplexes or a group that enhances the pharmacokinetic properties of cross-linked duplexes. 53. The method of claim 51 including selecting said cross-linkage from imine, amine, aminoalkylamine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide- hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal, thiohemiacetal, α-keto-alkylthioalkyl or α-keto-alkyl- aminoalkyl linkages. 54. The method of claim 48 including selecting said sequence of nucleotides of said first site to be complementary to and specifically hybridizable with said sequence of nucleotides of said second site. 55. A method for cross-linking a single oligonucleotide comprising: selecting a first nucleotide sequence in an oligonucleotide; selecting a second nucleotide sequence in said oligonucleotide; incorporating an abasic nucleotide within said first nucleotide sequence; attaching a bond precursor on a nucleotide of said second sequence; and forming a covalent cross-linkage between said abasic site and said bond precursor. 56. The method of claim 55 including attaching said «. bond precursor on the sugar moiety of said second seσuence nucleotide. 57. The method of claim 55 including attaching said bond precursor on a 2'-position of said second nucleotide. 58. The method of claim 55 including: forming an aldehydic functional group at said abasic site; and selecting said bond precursor to include a functional group capable of forming one of an oxime, imine, hydrazone, hydrazide-hydrazone, semicarbazone, thiosemicarbazone, hemiacetal or thio-hemiacetal covalent linkage with said abasic site aldehydic functional group. 59. The method of claim 55 including selecting said first nucleotide sequence to be complementary to and specifically hybridizable with said second nucleotide sequence. 60. A method of cross-linking a single oligonucleotide strand comprising: selecting a first nucleotide sequence in an oligo¬ nucleotide; selecting a second nucleotide sequence in said oligonucleotide; attaching a first bond precursor to the sugar moiety of a first nucleotide of said first nucleotide sequence; attaching a second bond precursor to the sugar moiety of a second nucleotide of said second nucleotide sequence; and forming a covalent cross-linkage between said first and said second bond precursors. 61. The method of claim 60 including selecting said first nucleotide sequence to be complementary to and specifically hybridizable with said second nucleotide sequence. 62. The method of claim 60 including selecting said covalent cross-linkage from imine, amine, aminoalkylamine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide- hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal or thiohemiacetal linkages, 63. A method of cross-linking first and second strands of oligonucleotides comprising: selecting a first nucleotide sequence in a first oligonucleotide strand; selecting a second nucleotide sequence in a second oligonucleotide strand; incorporating an abasic nucleotide within said first nucleotide sequence; attaching a bond precursor to a nucleotide of said second nucleotide sequence; and forming a covalent cross-linkage between said abasic site and said bond precursor. 64. The method of claim 63 including selecting said first nucleotide sequence to be complementary to and specifically hybridizable with said second nucleotide sequence. 65. The method of claim 63 including attaching said sequence bond precursor to the sugar moiety of said second sequence nucleotide. 66. The method of claim 65 including attaching said bond precursor to a 2' -position of said second nucleotide. 67. The method of claim 63 including: forming an aldehydic functional group at said abasic site; and. selecting said """" bond precursor to include a functional group capable of forming one of an oxime, imine, hydrazone, semicarbazone, thiosemicarbazone, hydrazide- hydrazone, hemiacetal or thiohemiacetal linkage with said abasic site aldehydic functional group. 68. A method of cross-linking first and second strands of oligonucleotides comprising: selecting a first nucleotide sequence in a first oligonucleotide strand; selecting a second nucleotide sequence in a second oligonucleotide strand; attaching a first bond precursor to the sugar moiety of a selected nucleotide of said first nucleotide sequence; attaching a second bond precursor to the sugar moiety of a nucleotide of said second nucleotide sequence; and forming a covalent cross-linkage between said first and said second bond precursors. 69. The method of claim 68 including selecting said first nucleotide sequence to be complementary to and specifically hybridizable with said second nucleotide sequence. 70. The method of claim 68 including choosing said covalent cross-linkage from imine, amine, aminoalkylamine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide- hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal or thiohemiacetal linkages. AMENDED CLAIMS [received by the International Bureau on 1 July 1993 (01-07.93); original claims 2-5, 8-11, 15-18, 21, 23, 24, 25, 30, 48, 60 and 68 amended other claims unchanged (24 pages)] 1. A cross-linked nucleic acid comprising: a first nucleotide located on a first oligonucleotide strand, said first nucleotide being covalently bound to at least two further nucleotides on said first oligonucleotide strand; a first bond means located on a sugar moiety of said first nucleotide; a second nucleotide located on a further oligonucleotide strand, said second nucleotide being covalently bound to at least two further nucleotides on said further oligonucleotide strand; a second bond means located on a sugar moiety of said second nucleotide; and a covalent cross-linkage between said first and said second bond means. 2. A cross-linked nucleic acid comprising: a first nucleotide located on an oligonucleotide strand, said first nucleotide being covalently bound to at least two further nucleotides on said oligonucleotide strand; a first bond means located on a sugar moiety of said first nucleotide; a second nucleotide located on said oligonucleotide strand, said second nucleotide being covalently bound to at least two further nucleotides on said oligonucleotide strand different from said first nucleotide; a second bond means located on a sugar moiety of said second nucleotide; and a covalent cross-linkage between said first and said second bond means. 3. A cross-linked nucleic acid comprising: a first nucleotide located on a 3' end of a first oligonucleotide strand, said first nucleotide including a 2' ,3' -dialdehyde structure; a second nucleotide located on a further oligonucleo¬ tide strand or on said first oligonucleotide strand; a space-spanning group located on a sugar moiety of said second nucleotide; and a covalent cross-linkage between said dialdehyde structure and said space-spanning group. 4. A cross-linked nucleic acid comprising: a first nucleotide located on a 3' end of a first oligonucleotide strand, said first nucleotide including 2' and 3' hydroxyl groups; a second nucleotide located on a further oligonucleotide strand or on said first oligonucleotide strand; a space-spanning group located on a sugar moiety of said second specific nucleotide; and a covalent acetal cross-linkage between said 2' and 3' hydroxyl groups and said space-spanning group. 5. A cross-linked nucleic acid comprising: a first nucleotide located on a first oligonucleotide strand, said first nucleotide being covalently bound to at least two further nucleotides on said first oligonucleotide strand; a first bond means located on a sugar moiety of said first nucleotide; a second nucleotide located on a further oligonucleo¬ tide strand or on said first oligonucleotide strand, said second nucleotide being covalently bound to at least two further nucleotides on said further oligonucleotide strand or said first oligonucleotide strand; a second bond means located on said second nucleotide; and a covalent cross-linkage between said first and said second bond means. 6. The cross-linked nucleic acid of claim 5 wherein: said first nucleotide is located in a first nucleotide sequence and said second nucleotide is located in a second nucleotide sequence; said second nucleotide sequence is complementary to and hybridizable with said first nucleotide sequence and said first and said second nucleotide sequences are located on a single strand of said oligonucleotide with said second nucleotide sequence located on said oligonucleotide at a distance separated from said first nucleotide sequence sufficient to allow said oligonucleotide to assume a conformation wherein said first and second nucleotide sequences are mutually aligned with and specifically hybridized with one another. 7. The cross-linked nucleic acid of claim 5 wherein: said first nucleotide is located in a first nucleotide sequence and said second nucleotide is located in a second nucleotide sequence; said second nucleotide sequence is complementary to and specifically hybridizable with said first nucleotide sequence; and said first and said second nucleotide sequences are located on different oligonucleotide strands. 8. The cross-linked nucleic acid of claim 5 wherein: said first bond means includes an abasic site; and said second bond means includes a space-spanning group covalently bonded with said abasic site. 9. The cross-linked nucleic acid of claim 8 wherein said abasic site includes an aldehyde. 10. The cross-linked nucleic acid of claim 8 wherei said space-spanning group includes an amine, hydrazine, hydroxylamine, semicarbazide, thiosemicarbazide, hydrazone, hydrazide, alcohol or thiol. 11. The cross-linked nucleic acid of claim 10 wherein said space -spanning group includes an amine . 12 . The cross-linked nucleic acid of claim 8 wherein said space -spanning group is attached to a 2 ' -position of said second nucleotide . 13 . The cross-linked nucleic acid of claim 8 wherein said space -spanning group is C 1 -C 20 straight chain alkyl , C 1 -C 20 straight chain O-alkyl , C 1 -C 20 straight chain S-alkyl , C__-C 2Q straight chain NH-alkyl , C x -C 20 straight chain substituted alkyl , C- L -C^ straight chain substituted O-alkyl , ^C^ straight chain substituted S-alkyl , C 1 -C 20 straight chain substituted NH-alkyl , C 2 -C 50 branched chain alkyl , C 2 -C 50 branched chain 0-alkyl , C 2 -C 50 branched chain S- alkyl , C 2 -C 50 branched chain NH-alkyl , C 2 -C 50 branched chain substituted alkyl , C 2 -C 50 branched chain substituted O-alkyl , C 2 -C 50 branched chain substituted S-alkyl , C 2 -C 50 branched chain substituted NH-alkyl , C 2 -C 20 straight chain alkenyl , C 2 -C 20 straight chain O-alkenyl , C 2 -C 20 straight chain S-alkenyl , C 2 -C 20 straight chain NH-alkenyl , C 2 -C 20 straight chain substituted alkenyl , C 2 -C 20 straight chain substituted O-alkenyl , C 2 -C 20 straight chain substituted S-alkenyl , C 2 -C 20 straight chain substituted NH-alkenyl , C 3 -C 50 branched chain alkenyl , C 3 -C 50 branched chain O-alkenyl, C 3 -C 50 branched chain S-alkenyl , C 3 -C 50 branched chain NH-alkenyl , C 3 -C 50 branched chain substituted alkenyl , C 3 -C 50 branched chain substituted O-alkenyl , C 3 -C 50 branched chain substituted S-alkenyl , C 3 -C 50 branched chain substituted NH-alkenyl , C 2 -C 20 straight chain alkyne , C 2 -C 20 straight chain O-alkyne, C 2 -C 20 straight chain S-alkyne, C 2 -C 20 straight chain NH-alkyne, C 2 -C 20 straight chain substituted alkyne, C 2 -C 20 straight chain substituted O-alkyne , C 2 -C 20 straight chain substituted S-alkyne , C 2 -C 20 straight chain substituted NH-alkyne, C 3 -C 50 branched chain alkyne, C 2 -C 50 branched chain O-alkyne, C 3 -C 50 branched chain S-alkyne, C 3 -C 50 branched chain NH-alkyne, C 3 -C 3o branched chain substituted alkyne, C 3 -C 50 branched chain substituted O-alkyne, C 3 -C 50 branched chain substituted S-alkyne, C 3 -C S0 branched chain substituted NH-alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic. 14. The cross-linked nucleic acid of claim 13 wherein said space-spanning group is from about 8 to about 13 atoms in length. 15. The cross-linked nucleic acid of claim 5 wherein: said first bond means includes a first space-spanning group; said second bond means includes a second space- spanning group; and said covalent cross-linkage is between said first and said second space-spanning groups. 16. The cross-linked nucleic acid of claim 15 wherein said first space-spanning group is an aldehyde, a protected aldehyde or an aldehyde precursor. 17. The cross-linked nucleic acid of claim 16 wherein said first space-spanning group is C-formyl, o-methylamino- benzenethiol, aryl substituted imidazolidino, dithiane, bis(p- nitrophenoxy) , acetal, nitrile, ester or alcohol. 18. The cross-linked nucleic acid of claim 15 wherein said second space-spanning group is an amine, hydrazine, hydroxylamine, semicarbazide, thiosemicarbazide, hydrazide, alcohol or thiol. 19 . The cross-linked nucleic acid of claim 15 wherein : said first space -spanning group is attached to a 2 ' - position of said first nucleotide ; and said second space -spanning group is attached to a 2 ' - position of said second nucleotide . 20 . The cross-linked nucleic acid of claim 15 wherein each of said first and second space -spanning groups are, independently, C- . -^ straight chain alkyl , C x -C 20 straight chain O-alkyl , C 1 -C 20 straight chain S-alkyl , L -C^ straight chain NH- alkyl , C- L -C,,- straight chain substituted alkyl , C ± -C 20 straight chain substituted O-alkyl , C^C^ straight chain substituted S- alkyl , C- L - JO straight chain substituted NH-alkyl , C 2 -C 50 branched chain alkyl , C 2 -C 50 branched chain O-alkyl , C 2 -C 50 branched chain S-alkyl , C 2 -C 50 branched chain NH-alkyl , C 2 -C 50 branched chain substituted alkyl , C 2 -C 50 branched chain substituted O-alkyl , C 2 -C 50 branched chain substituted S-alkyl , C 2 -C 50 branched chain substituted NH-alkyl , C 2 -C 20 straight chain alkenyl , C 2 -C 20 straight chain O-alkenyl , C 2 -C 20 straight chain S-alkenyl, C 2 -C 20 straight chain NH-alkenyl , C 2 -C 20 straight chain substituted alkenyl , C 2 -C 20 straight chain substituted O- alkenyl , C 2 -C 20 straight chain substituted S-alkenyl , C 2 -C 20 straight chain substituted NH-alkenyl , C 3 -C 50 branched chain alkenyl , C 3 -C 50 branched chain O-alkenyl , C 3 -C 50 branched chain S-alkenyl , C 3 -C 50 branched chain NH-alkenyl , C 3 - C so branched chain substituted alkenyl , C 3 -C 50 branched chain substituted O-alkenyl , C 3 -C 50 branched chain substituted S- alkenyl , C 3 -C S0 branched chain substituted NH-alkenyl , C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain O-alkyne , C 2 -C 20 straight chain S-alkyne, C 2 -C 20 straight chain NH-alkyne , C 2 -C 20 straight chain substituted alkyne, C 2 -C 20 straight chain substi¬ tuted O-alkyne, C 2 -C 20 straight chain substituted S-alkyne, C 2 - C 20 straight chain substituted NH-alkyne, C 3 -C 50 branched chain alkyne, C 2 -C 50 branched chain O-alkyne, C 3 -C 50 branched chain S- alkyne, C 3 -C 50 branched chain NH-alkyne, C 3 -C 50 branched chain substituted alkyne, C 3 -C 50 branched chain substituted O-alkyne, C a -C 50 branched chain substituted S-alkyne, C 3 -C 50 branched chain substituted NH-alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic. 21. The cross-linked nucleic acid of claim 15 wherein said first and second space-spanning groups are thiol groups and said covalent cross-linkage is a disulfide bond. 22. The cross-linked nucleic acid of claim 5 wherein: said first nucleotide is located in a first nucleotide sequence and said second nucleotide is located in a second nucleotide sequence; and said first and said second nucleotide sequences are located on a single strand of an oligonucleotide with said second nucleotide sequence located on said oligonucleotide at a non-hybridizable position with respect to said first nucleotide sequence and at a distance from said first nucleotide sequence sufficient to allow said oligonucleotide to assume a conformation wherein said first and second nucleotide sequences are located in spatial proximity with each other. 23. The cross-linked nucleic acid of claim 5 wherein: said first bond means includes a 3'-terminal nucleoside having a 2' ,3'-dialdehyde structure; said second bond means includes a space-spanning group; and said active functional group is capable of reacting with a dialdehyde. 24. The cross-linked nucleic acid of claim 5 wherein: said first bond means includes a 3'-terminal nucleotide having 2' and 3'-sugar hydroxyl groups; said second bond means includes a space-spanning group; and an acetal cross-linkage connects said 2' and 3' hydroxyl groups and said space-spanning group. 25. A cross-linked oligonucleotide comprising: a first sequence region in an oligonucleotide; a second sequence region in an oligonucleotide; an abasic site located in said first sequence region; and a space-spanning group located on said second sequence region and covalently bonded with said abasic site. 26. The cross-linked oligonucleotide of claim 25 wherein said first sequence region and said second sequence region are on a single oligonucleotide strand. 27. The cross-linked oligonucleotide of claim 25 wherein said first sequence region and said second sequence r- egion are on different oligonucleotide strands. 28. The cross-linked oligonucleotide of claim 25 wherein said first sequence region and said second sequence r- egion are complementary to and specifically hybridizable with one another. 29. The cross-linked oligonucleotide of claim 25 wherein said space-spanning group is C x -C 20 straight chain alkyl, C- L -C 20 straight chain O-alkyl, C- ^ -C ao straight chain S- alkyl, ~ r ~ ~ . straight chain NH-alkyl, C α -C 20 straight chain substituted alkyl, C 1 -C 20 straight chain substituted O-alkyl, L -C 20 straight chain substituted S-alkyl, C^C-,,, straight chain substituted NH-alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain O-alkyl, C 2 -C 50 branched chain S-alkyl, C 2 -C 50 branched chain NH-alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 50 branched chain substituted O-alkyl, C 2 -C 50 branched chain substituted S-alkyl, C 2 -C 50 branched chain substituted NH- alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain O- alkenyl, C 2 -C 20 straight chain S-alkenyl , C 2 -C 20 straight chain NH-alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 2 -C 20 straight chain substituted O-alkenyl, C 2 -C 20 straight chain substituted S-alkenyl, C 2 -C 20 straight chain substituted NH- alkenyl, C 3 -C 50 branched chain alkenyl , C 3 -C 50 branched chain O- alkenyl, C 3 -C 50 branched chain S-alkenyl, C 3 -C 50 branched chain NH-alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 3 -C 50 branched chain substituted O-alkenyl, C 3 -C 50 branched chain substituted S-alkenyl, C 3 -C 50 branched chain substituted NH- alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain 0- alkyne, C 2 -C 20 straight chain S-alkyne, C 2 -C 20 straight chain NH- alkyne, C 2 -C 20 straight chain substituted alkyne, C 2 -C 20 straight chain substituted O-alkyne, C 2 -C 20 straight chain substituted S- alkyne, C 2 -C 20 straight chain substituted NH-alkyne, C 3 -C 50 branched chain alkyne, C 2 -C 50 branched chain O-alkyne, C 3 -C 50 branched chain S-alkyne, C 3 -C 50 branched chain NH-alkyne, C 3 -C 30 branched chain substituted alkyne, C 3 -C 50 branched chain sub¬ stituted O-alkyne, C 3 -C 50 branched chain substituted S-alkyne, C 3 -C 50 branched chain substituted NH-alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic . 30. The cross-linked oligonucleotide of claim 25 wherein said space -spanning group includes an amine, hydrazine, hydroxylamine, semicarbazide, hydrazide, alcohol or thiol . 31. The cross-linked oligonucleotide of claim 25 wherein said space- spanning group is CH 2 -L 3 , 0-L 3 , S-L 3 , NH-L 3 or CO-L 3 where L 3 is C -C 20 straight chain alkyl, C 1 -C 20 straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic. 32. The cross-linked oligonucleotide of claim 25 wherein said space-spanning group is located on a 2'-position of a nucleotide within said second sequence region. 33. A cross-linked oligonucleotide comprising: a first sequence region in an oligonucleotide,- a second sequence region in an oligonucleotide; and a covalently bonded linker of the structure: wherein X x is covalently connected to said first sequence re¬ gion, X 2 is covalently connected to said second sequence region, and where: (i) X x and X 2 , independently, are 0, S, NH, CH 2 or CO; L- . and L 2 , independently, are C 1 -C 20 straight chain alkyl, C-__-C 2 __ straight chain substituted alkyl, C 2 -C 3o branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, polyether, aryl, aralkyl or heterocyclic; and Y is an imine, amine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide-hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal, thiohemiacetal, α-keto-alkylthioalkyl or α-keto-alkylaminoalkyl; or (ii) X x and X 2 , independently, are O or NH; and L 1 -Y-L 2 together are NH-L 3 -NH or NH-NH-L 3 -NH-NH; and L 3 is C 1 -C 20 straight chain alkyl, C 1 -C 20 straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, polyether, aryl, aralkyl or heterocyclic; or (iii) X and X 2 , independently, are O, S, NH, CH 2 or CO; L- L and L 2 , independently, are C- L -C 20 straight chain alkylamino, L -C^ straight chain substituted alkylamino, C 2 -C 50 branched chain alkylamino, C 2 -C 3o branched chain substituted alkylamino, C 2 -C 20 straight chain alkenylamino, C 2 -C 20 straight chain substituted alkenylamino, C 3 -C 50 branched chain alkenylamino, C 3 -C 50 branched chain substituted alkenylamino, C 2 -C 20 straight chain alkynylamino, C 2 -C 20 straight chain substituted alkynylamino, ~ j ~C 50 branched chain alkynylamino, C 3 -C 50 branched chain substituted alkynylamino, C 1 -C 20 straight chain alkylthio, C- L -C 20 straight chain substituted alkylthio, C 2 -C 50 branched chain alkylthio, C 2 -C 50t branched chain substituted alkylthio, C 2 -C 20 straight chain alkenylthio, C 2 -C 20 straight chain substituted alkenylthio, C 3 -C 50 branched chain alkenylthio, C 3 -C S0 branched chain substituted alkenylthio, C 2 -C 20 straight chain alkynylthio, C 2 -C 20 straight chain substituted alkynylthio, C 3 -C Ξ0 branched chain alkynylthio or C 3 -C 50 branched chain substituted alkynylthio; and Y is a heterobifunctional or homobifunctional cross-linking reagent; where said substituent of said substituted alkyl, substituted alkenyl and substituted alkyne moieties is an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that enhances the pharmacodynamic properties of oligonucleotides or a group that enhances the pharmacokinetic properties of oligonucleotides. 34. The cross-linked oligonucleotide of claim 33 wherein: X α and X 2 , independently, are O, S, NH, CH 2 or CO; L-_ and L 2 , independently, are C 1 -C 20 straight chain alkyl, C 1 -C 20 straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50ι branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic; and Y is imine, amine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide-hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal, thiohemiacetal, α-keto-alkylthioalkyl or x-keto-alkylaminoalkyl. 35. The cross-linked oligonucleotide of claim 34 wherein x and X 2 , independently, are 0, S or NH. 36. The cross-linked oligonucleotide of claim 34 wherein Y is imine, amine, oxime, hydrazine, hydrazone or hydroxylamine. 37. The cross-linked oligonucleotide of claim 34 wherein Y is disulfide. 38. The cross-linked oligonucleotide of claim 33 wherein: X- L and X 2 , independently, are 0 or NH; together L-^Y-L a are HN-L 3 -NH; and L 3 is C- L -C JO straight chain alkyl, Q L -C JO straight chain substituted alkyl, C 2 -C 50 branched chain alkyl, C 2 -C 50 branched chain substituted alkyl, C 2 -C 20 straight chain alkenyl, C 2 -C 20 straight chain substituted alkenyl, C 3 -C 50 branched chain alkenyl, C 3 -C 50 branched chain substituted alkenyl, C 2 -C 20 straight chain alkyne, C 2 -C 20 straight chain substituted alkyne, C 3 -C 50 branched chain alkyne, C 3 -C 50 branched chain substituted alkyne, polyamine, polyamide, polyester, polyethylene glycol, aryl, aralkyl or heterocyclic. 39. The cross-linked oligonucleotide of claim 38 wherein X x and X 2 are 0. 40. The cross-linked oligonucleotide of claim 38 wherein L 3 is polymethylene. 41. The cross-linked oligonucleotide of claim 33 wherein said first sequence region and said second sequence region, are on a single oligonucleotide strand. 42. The cross-linked oligonucleotide of claim 33 wherein said first sequence region and said second sequence region are on different oligonucleotide strands. 43. The cross-linked oligonucleotide of claim 33 wherein: X x and X 2 , independently, are 0, S, NH, CH 2 or CO; Lj, and L 2 , independently, are C 1 -C 20 straight chain alkylamino, C^C ao straight chain substituted alkylamino, C 2 -C 50 branched chain alkylamino, C 2 -C 50 branched chain substituted alkylamino, C 2 -C 20 straight chain alkenylamino, C 2 -C 20 straight chain substituted alkenylamino, C 3 -C 50 branched chain alkenylamino, C 3 -C 50 branched chain substituted alkenylamino, C 2 -C 20 straight chain alkynylamino, C 2 -C 20 straight chain substituted alkynylamino, C 3 -C 50 branched chain alkynylamino, C 3 -C 50 branched chain substituted alkynylamino, C- . -C 20 straight chain alkylthio, C 1 -C 20 straight chain substituted alkylthio, C 2 -C 50 branched chain alkylthio, C 2 -C 50 branched chain substituted alkylthio, C 2 -C 20 straight chain alkenylthio, C 2 -C 20 straight chain substituted alkenylthio, C 3 -C 50 branched chain alkenylthio, C 3 -C 50 branched chain substituted alkenylthio, C 2 - C 20 straight chain alkynylthio, C 2 -C 20 straight chain substituted alkynylthio, C 3 -C 50 branched chain alkynylthio or C 3 -C 50 branched chain substituted alkynylthio; and Y is a heterobifunctional or homobifunctional cross- linking reagent. 44. The cross-linked oligonucleotide of claim 43 wherein Y is a heterobifunctional cross-linking reagent comprising two reactive moieties independently selected from maleimide, N-hydroxysuccinimide, N-hydroxysulfosuccinimide, imidoester, pyridyl disulfide, β-carbony1 alkylhalide or photoreactive aryl azide. 45. A cross-linked oligonucleotide comprising: a first sequence region in an oligonucleotide; a second sequence region in an oligonucleotide; a first space-spanning group connected to a 2'- position of a nucleotide located in said first sequence region; a second space-spanning group connected to a 2'- position of a nucleotide located on said second sequence region; and a linking moiety covalently bonding said first and second space-spanning groups. 46. The cross-linked oligonucleotide of claim 45 wherei : said linking moiety is -N=CH-, -N(R) -CH 2 -N(R) -, -N(R) -, -0-N=CH-, -O-N(R) -, -N(R) -N(R) -, -HC=N-N(R) -, -HC=N-N=CH-, -C(0)-N(R) -N=CH-, -C(0)N(R)-, -C(0) -N(R) -N(R) -, -N(R) -C(0) -N(R) -N(R) -, -N(R) -C(0) -N(R) -N=CH-, -N(R) -C(S)-N(R) -N(R) -, -N(R) -C(S) -N(R) -N=CH-, -S-S-, -CH(OH) -0-CH 2 -, -CH(OH) -S-CH 2 -, -CH 2 -S-CH 2 -C(0) -CH 2 - or -CH 2 -NH-CH 2 -C(0) -CH 2 -; and R is H, alkyl, alkenyl, aralkyl, an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that enhances the pharmacodynamic properties of oligonucleotides or a group that enhances the pharmacokinetic properties of oligonucleotides. 47. The cross-linked oligonucleotide of claim 46 wherein is H. 48. A method of fixing an oligonucleotide in a set configuration c mprising: selecting a first site in said oligonucleotide, said first site having a first nucleotide sequence; attaching a first bond precursor to the sugar moiety of a first nucleotide of said first site, said first nucleotide being covalently bound to at least two further nucleotides in said first nucleotide sequence; selecting a second site in said oligonucleotide, said second, site having a second nucleotide sequence; attaching a second bond precursor to the sugar moiety of a second nucleotide of said second site, said second nucleotide being covalently bound to at least two further nucleotides in said second nucleotide sequence; and forming a covalent cross-linkage between said first and said second bond precursors. 49. The method of claim 48 including: attaching said first bond precursor to said first nucleotide by reacting a precursor of said first nucleotide with a reagent for introducing said first bond precursor on the sugar moiety of said first nucleotide precursor; derivatizing said first nucleotide precursor to a protected and activated form; synthetically incorporating said derivatized first nucleotide precursor into said first nucleotide sequence; attaching said second bond precursor to said second nucleotide by reacting a precursor of said second nucleotide with a reagent for introducing said second bond precursor on the sugar moiety of said second nucleotide precursor; derivatizing said second nucleotide precursor to a protected and activated form; and synthetically incorporating said derivatized second nucleotide precursor into said second nucleotide sequence. 50. The method of claim 48 including: selecting an abasic nucleotide as said first bond precursor; and attaching said ' second bond precursor to a 2'-position of said second nucleotide. 51. The method of claim 48 including: attaching said first bond precursor to a 2'-position of said first nucleotide; and attaching said second bond precursor to a 2'-position of said second nucleotide. 52. The method of claim 51 including selecting said cross-linkage from: -N=CH-, -N(R)-, -N(R) -CH 2 -NH-, -NH-CH 2 -NH-, -0-N=CH-, -O-N(R)-, -N(R)-N(R)-, -HC=N-N(R)-, -HC=N-N=CH-, -C(0) -N(R) -N=CH-, -C(0)N(R)-, -C(O)- N(R)-N(R)-, -N(R)-C(0) -N(R)-N(R)-, -N(R) -C(0) -N(R) -N=CH-, -N(R) -C(S) -N(R) -NH-, -N(R) -C(S) -N(R) -N=CH-, -S-S-, -CH(OH) -0-CH 2 -, -CH(OH) -S-CH 2 -, -CH 2 -S-CH 2 - C(0)-CH 2 - or -CH 2 -NH-CH 2 -C(0) -CH 2 -; wherein R is H, alkyl, alkenyl, aralkyl, an intercalator, a conjugate, polyamine, polyamide, polyethylene glycol, a group that enhances the pharmacodynamic properties of cross-linked duplexes or a group that enhances the pharmacokinetic properties of cross-linked duplexes. 53. The method of claim 51 including selecting said cross-linkage from imine, amine, aminoalkylamine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide- hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal, thiohemiacetal, α-keto-alkylthioalkyl orc-keto-alkylaminoalkyl linkages. 54. The method of claim 48 including selecting said sequence of nucleotides of said first site to be complementary to and specifically hybridizable with said sequence of nucleotides of said second site. 55. A method for cross-linking a single oligonucleotide comprising: selecting a first nucleotide sequence in an oligonucleotide; selecting a second nucleotide sequence in said oligonucleotide; incorporating an abasic nucleotide within said first nucleotide sequence; attaching a bond precursor on a nucleotide of said second sequence; and forming a covalent cross-linkage between said abasic site and said bond precursor. 56. The method of claim 55 including attaching said bond precursor on the sugar moiety of said second sequence nucleotide. 57. The method of claim 55 including attaching said bond precursor on a 2'-position of said second nucleotide. 58. The method of claim 55 including: forming an aldehydic functional group at said abasic site; and selecting said bond precursor to include a functional group capable of forming one of an oxime, imine, hydrazone, hydrazide-hydrazone, semicarbazone, thiosemicarbazone, hemi¬ acetal or thio-hemiacetal covalent linkage with said abasic site aldehydic functional group. 59. The method of claim 55 including selecting said first nucleotide sequence to be complementary to and specifically hybridizable with said second nucleotide sequence. 60. A method of cross-linking a single oligonucleotide strand comprising: selecting a first nucleotide sequence in an oligo¬ nucleotide; selecting a second nucleotide sequence in said oligonucleotide; attaching a first bond precursor to the sugar moiety of a first nucleotide that is covalently bound to at least two further nucleotides in said first nucleotide sequence; attaching a second bond precursor to the sugar moiety of a second nucleotide that is covalently bound to at least two further nucleotides in said second nucleotide sequence; and forming a covalent cross-linkage between said first and said second bond precursors. 61. The method of claim 60 including selecting said first nucleotide sequence to be complementary to and specifically hybridizable with said second nucleotide sequence. 62. The method of claim 60 including selecting said covalent cross-linkage from imine, amine, aminoalkylamine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide- hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal or thiohemiacetal linkages, 63. A method of cross-linking first and second strands of oligonucleotides comprising: selecting a first nucleotide sequence in a first oligonucleotide strand; selecting a second nucleotide sequence in a second oligonucleotide strand; incorporating an abasic nucleotide within said first nucleotide sequence; attaching a bond precursor to a nucleotide of said second nucleotide sequence; and forming a covalent cross-linkage between said abasic site and said bond precursor. 64. The method of claim 63 including selecting said first nucleotide sequence to be complementary to and specifically hybridizable with said second nucleotide sequence. 65. The method of claim 63 including attaching said sequence bond precursor to the sugar moiety of said second sequence nucleotide. 66. The method of claim 65 including attaching said bond precursor to a 2'-position of said second nucleotide. 67. The method of claim 63 including: forming an aldehydic functional group at said abasic site; and selecting said bond precursor to include a functional group capable of forming one of an oxime, imine, hydrazone, semicarbazone, thiosemicarbazone, hydrazide-hydrazone, hemiacetal or thiohemiacetal linkage with said abasic site aldehydic functional group. 68. A method of cross-linking first and second strands of oligonucleotides comprising: selecting a first nucleotide sequence in a first oligonucleotide strand; selecting a second nucleotide sequence in a second oligonucleotide strand; attaching a first bond precursor to.the sugar moiety of a first nucleotide that is covalently bound to at least two further nucleotides in said first nucleotide sequence; attaching a second bond precursor to the sugar moiety of a second nucleotide that is covalently bound to at least two further nucleotides in said second nucleotide sequence; and forming a covalent cross-linkage between said first and said second bond precursors. 69. The method of claim 68 including selecting said first nucleotide sequence to be complementary to and specifically hybridizable with said second nucleotide sequence. 70. The method of claim 68 including choosing said covalent cross-linkage from imine, amine, aminoalkylamine, oxime, hydroxylamine, hydrazine, hydrazone, azine, hydrazide- hydrazone, amide, hydrazide, semicarbazide, semicarbazone, thiosemicarbazide, thiocarbazone, disulfide, hemiacetal or thiohemiacetal linkages. STATEMENT UNDER ARTICLE 19 Further to the International Search Report mailed April 28, 1993 in connection with this patent application, Applicants have amended the claims to specify nucleotides covalent bonding at the site of a cross-linkage. The claims also have been amended to more clearly define the invention with respect to the role of space-spanning groups in the formation of covalent cross-linkages. These amendments find support in the specification at, for example, page 6, lines 32-36, page 7, line 36 - page 8, line 14, and page 16, line 18 - page 17, line 3.

Inventors: BRUICE THOMAS, COOK PHILLIP DAN, MANOHARAN MUTHIAN, BRUICE, THOMAS, COOK, PHILLIP, DAN, MANOHARAN, MUTHIAN
Applicants: ISIS PHARMACEUTICALS INC, ISIS PHARMACEUTICALS, INC.
Application year: 1993
Main classification: C07H21
IPC codes: C07H21, C12N15