HAIRPIN HYBRIDIZER MOLECULES FOR MODULATION OF GENE EXPRESSION

Abstract: The invention features novel hairpin hybridizer nucleic acid molecules which are able to modulate gene expression; useful in target validation, gene function identification and in human therapeutics.

Description: DESCRIPTION HAIRPIN HYBRIDIZER MOLECULES FOR MODULATION OF GENE EXPRESSION Related Applications 5 This patent application claims the benefit of Hartmann et al, USSN 60/101,174, filed September 21, 1998 entitled "HAIRPIN HYBRIDIZER MOLECULES FOR MODULATION OF GENE EXPRESSION." This application is hereby incorporated by reference herein in its entirety including the drawings. Background of the Invention I O This invention relates to nucleic acid molecules, which the Applicant terms "hairpin hybridizer" (HPH) molecules that are capable of modulating gene expression by hybridizing to target RNA with improved specificity to thereby block translation of such target RNA. The following is a discussion of relevant art, none of which is admitted to be i 5 prior art to the present invention. Since the discovery of the mechanisms underlying gene expression, specifically nucleic acid based transcription and translation, a great deal of effort has been placed on blocking or altering these processes for a variety of purposes, such as understanding biology, gene function, disease processes, and identifying novel therapeutic targets. o Approaches involving the use of nucleic acid molecules for modulating gene expression have gained popularity in recent years. For example, nucleic acid molecules have been designed which are capable of binding to specific mRNA sequences by Watson-Crick base-pairing interaction and blocking translation (Crooke, 1996, Medicinal Res. Rev. 16, 319-344). Another approach involves complexation of DNA with triplex-forming oligonucleotides to prevent transcription of bound DNA sequences thereby inhibiting gene expression (Kim et al., 1998, Biochemistry. 37, 2299-2304). The interaction of antisense oligonucleotides, 2-5A antisense chimera, or ribozymes with target RNAs have been used to modulate gene expression. All of these nucleic acid molecules are 5 highly specific to their matching target sequences and therefore may offer lower toxicity compared to traditional approaches such as chemotherapy. The concept of gene expression inhibition through an antisense mechanism is derived in part from mechanisms found in nature. It was found that prokaryotic systems utilized complementary RNA molecules to inhibit translation (Lacetena et al., i o 1983, Blood 170, 635-650). Simons et al., 1983, Cell 34, 673-682; Mizuno et al, 1984, Proc. Natl. Acad Sci. (USA) 81, 1966-1970). For example, expression of E. coli OmpF and OmpC genes (outer membrane proteins) is regulated by an antisense RNA mechanism (Mukopadhyay & Roth, 1996, Critical Rev. In Oncogenesis 7, 151-190). Antisense oligonucleotides can be used to down-regulate target mRNA by a 1 5 number of different mechanisms. The specificity of these reagents is determined by the primary sequence (GC content, sequence length), chemistry (ribonucleotides, deoxy- ribonucleotides, chemically modified nudeotides) of the antisense molecule and the presence of pseudo-target sequences. Pseudo-targets are nucleic acid sequences, which may have sequence identity or homology to a target sequence. The number of pseudo- o targets for a given sequence, especially human genes, is largely unknown at this point, since only a minor fraction of the human genome is currently sequenced. Lizardi et al, US Patent No. 5,312,728, describe a self hybridizing nucleic acid molecule, referred to as a molecular switch used, for the detection of target nucleic acid molecules. The molecular switch consists of a probe sequence of 20 to 60 nudeotides 25 capable of hybridizing to a target sequence and 5' and 3' sequences of at least 10 nudeotides in length which are capable of hybridizing to each other intrarnolecularly. Εngdahl et al, 1997, Nucleic Acids Research 25, 3218-3227, describe the use of an RNA cassette system for silencing the lad gene. The molecules used consisted of a hairpin structure, which was used for target sequence recognition and an inhibitor region which was either an antisense or ribozyme sequence. Delihas et al., 1997, Nature Biotech 15, 751-753, describe the formation of noι canonical base-pairs using natural antisense RNA and target RNA. 5 Stinchcomb et al, International PCT Publication NO. WO 95/23225, describe an RNA molecule with an intramolecular stem-loop structure of greater than or equal to eight base-pairs. Summary of the Invention This invention relates to nucleic acid molecules capable of binding and blocking i o the function of target nucleic acid molecules, thereby modulating cellular or viral mechanisms including splicing, editing, replication or gene expression, and translation. Specifically, the invention concerns novel nucleic acid molecules with a hairpin- secondary structure capable of down regulating protein expression by binding (steric blocker) and optionally facilitating the cleavage of target RNA through an RNase H or 1 5 other mechanism. For simplicity and ease of understanding the instant invention, the nucleic acid molecules of the instant invention shall be referred to as hairpin hybridizer (HPH) molecules. In particular, applicant describes the use of these HPH molecules to down-regulate gene expression in bacterial, microbial, fungal, eukaryotic systems including plant, or mammalian cells. Down-regulation of specific target sequences may θ either have a therapeutic effect in many diseases or disease states or aid in the identification of gene function and/or new therapeutic gene targets. The HPH molecules of the present invention can be used for in vitro or in vivo applications well known in the art. The present invention features a method of modulating the function of a target 25 sequence in a cell using HPH molecules. HPH molecules include target-binding region and a hairpin region, where the target-binding region is capable of binding to the target sequence in a sequence specific manner in vitro or in vivo to modulate the function of the target sequence. The hairpin region of the HPH molecule provides an improved specificity characteristic to the HPH molecule. The hairpin region is expected ϊ provide improved resistance to nuclease degradation, is expected to help the HPH 5 molecule with localization inside a cell, and is expected to help in improved uptake of the HPH molecule by the cells compared to a molecule lacking such a hairpin structure. The target-binding region of the HPH molecule may also include an RNase H- activating region where such a region includes a greater than or equal to 4 deoxyribonucleotide nucleotide sequence with phosphorothioate, phosphodiester, I O phosphorodithioate, arabino, 2'-fluoro arabino-and/or 5'thiophosphate intemucleotide linkages. The RNase H-activating region interacts with the target RNA to form a DNA:RNA complex which is recognized by the cellular RNase H enzyme, which binds the DNA:RNA complex and cleaves the RNA portion of the DNA:RNA complex. Such cleavage of the target RNA by RNase H causes the target RNA to lose its normal i s function by causing inhibition of its translation into proteins, its replication, its packaging into viral particles, or other functions. Thus in a first aspect, a method of modulating the function, such as expression, of a target sequence, preferably in a cell, comprising the step of contacting said target sequence with a HPH nucleic acid molecule under conditions suitable for the 2o modulation of said target sequence expression, wherein the HPH nucleic acid molecule includes the following formulae: 25 Formula I: B B' where, each P, Y, N and M represents independently a nucleotide which may be 5 the same or different; • indicates hydrogen bond formation between two adjacent nudeotides, N' is a nucleotide complementary to N; o is an integer greater than or equal to 3, more specifically 4, 5, 6, 7, 8 or 9; k is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; t is zero or an integer greater than or equal to 3 and preferably less than about 100, I O more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; w is an integer greater than or equal to 4 and preferably less than 100, more specifically 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; (P) t and (P) are independently oligonucleotides, preferably including at least one position that is not deoxynucleotide (e.g. 2'-H containing nucleotide); (P), and (P) k may include phosphodiester, phosphorothioate, phosphorodithioate, 15 methylphosphonate linkers and the like or a combination thereof; k and t may be the same length (k=t) or different lengths (k ≠ t); (M) w is an oligonucleotide sequence whose inter-nucleotide linkers include phosphodiester, phosphorothioate, 5'thiophosphate, or methylphosphonate linkers or a combination thereof; t, k, and w may be of the same length (k = t = w) or different length (k ≠ t ≠ w) or (k = t ≠ w) or (k o ≠ t = w) or (k = w ≠ t); at least one or more of of each said (P)t, (P)k, and (M) w is an oligonucleotide of sufficient length to stably interact independently with a target sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); r and f are independently an integer greater than or equal to zero, specifically 1, 2, 3, 4, 5, 10, or 15; each B and B' independently represents a cap structure which may independently be present or absent; when r= 0, and f=0, B and/or B', when present, is attached to (N»N') 0 ; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5'-thiophosphate, methylphosphonate or others known in the art). i o Formula II: (M)w / \ (P)k (P)t (N • N')o / \ (P)k1 (P)t1 \ / (M)w where, each P, N, and M represents independently a nucleotide which may be same or different; • indicates hydrogen bond formation between two adjacent 15 nudeotides, N' is a nucleotide complementary to N; o is an integer greater than or equal to 3, more specifically 4, 5, 6, 7, 8 or 9; k is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; t is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; kl is zero or an integer greater 2o than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; tl is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; w is an integer greater than or equal to 4 and preferably less than 100, more specifically 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; (P) t and (P) k , (P) tl , and (P) kl are independently 5 oligonucleotides, preferably including at least one position that is not deoxynucleotide (e.g. 2'-H containing nucleotide); (P) t and (P) k , (P) tl , (P) kl may include phosphodiester, phosphorothioate, phosphorodithioate, 5'-thiophosphate, methylphosphonate linkers and the like or a combination thereof; k and t may be the same length (k=t) or different lengths (k ≠ t); kl and tl may be the same length (kl=tl) or different lengths (k ≠ t); I O (M) w is an oligonucleotide sequence whose inter-nucleotide linkers include phosphodiester, phosphorothioate, 5'thiophosphate, methylphosphonate, or phosphorodithioate linkers or a combination thereof; t, k, and w may be of the same length (k = t = w) or different length (k ≠ t ≠ w) or (k = t ≠ w) or (k ≠ t = w) or (k = w ≠ t); tl, kl, and w may be of the same length (kl = tl= w) or different length (kl ≠ tl ≠ i s w) or (kl = tl ≠ w) or (kl ≠ tl = w) or (kl = w ≠ tl); at least one or more of each said (P)„ (P) k , (P)„, (P) kl and (M) w is an oligonucleotide of sufficient length to stably interact independently with a target sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5'-thiophosphate, o methylphosphonate, or others known in the art). Formula III: (M)w (Ptø (P)t \ / (N • N')o \ B B' where, each P, N, and M represents independently a nucleotide which may be same or different; • indicates hydrogen bond formation between two adjacent 5 nudeotides, N' is a nucleotide complementary to N; o is an integer greater than or equal to 3, more specifically 4, 5, 6, 7, 8 or 9; k is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; t is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; w is an integer greater than or I O equal to 4 and preferably less than 100, more specifically 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; (P) t and (P) k are oligonucleotides preferably including at least one position that is not deoxynucleotide (e.g. 2'-H containing nucleotide); each(P), and (P) k may include phosphodiester, phosphorothioate, phosphorodithioate, 5'-thiophosphate, methylphosphonate linkers and the like or a combination thereof; k and t may be the i 5 same length (k=t) or different lengths (k ≠t); (M) w is an oligonucleotide sequence whose inter-nucleotide linkers may include phosphodiester, phosphorothioate, 5'thiophosphate, methylphosphonate, or phosphorodithioate linkers or a combination thereof; t, k, and w may be of the same length (k = t = w) or different length (k ≠ t ≠ w) or (k = t ≠ w) or (k ≠ t = w) or (k = w ≠ t); at least one or more of each said (P)t, (P)k, and (M) w is an oligonucleotide of sufficient length to stably interact independently with a target sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); D and E are oligonucleotides which are greater than or equal to 4 and preferably less than 100 nudeotides in length, more specifically 6, 7, 8, 9, 10, 11, 12, 15, 20, or 30 and are 5 of sufficient length to stably interact independently with a target sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); The D and E oligonucleotides may be symmetric (D = E in length) or asymmetric (D ≠ E in length); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, i o phosphorothioate, phosphorodithioate, 5'-thiophosphate, methylphosphonate or others known in the art). Formula IV: 15 where, N represents a ribonucleotide which may be the same or different; N' is a nucleotide complementary to N; • indicates hydrogen bond formation between two adjacent ribonucleotides; o is an integer greater than or equal to 3 and less than or equal to 9, more specifically 4, 5, 6, 7, 8 or 9; S, A, and B are oligoribonucleotides which are independently equal to 5 and preferably less than 100 nudeotides in length, more 2θ specifically 6, 7, 8, 9, 10, 11, 12, 15, 20, or 30; S is an oligonucleotide of sufficient length to stably interact independently with a target sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); and represents a phosphodiester linkage. Formula V: where, each P, N, F, V, Z, and M represents independently a nucleotide which may be same or different; • indicates hydrogen bond formation between two adjacent i o nudeotides, N' is a nucleotide complementary to N; F' is a nucleotide complementary to F; o is an integer greater than or equal to 3, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, or 15; k is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; t is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, i s 7, 8, 9, 10, 11, 12, 15, or 20; w is an integer greater than or equal to 4 and preferably less than 100, more specifically 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; d is an integer greater than or equal to 3 and preferably less than about 20, more specifically 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, or 18; h is an integer greater than or equal to 2 and preferably less than about 10, more specifically 2, 3, 4, 5, 6, 7, 8, or 9; c is an integer greater than 0 or equal to 0 and preferably less than about 20, more specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, or 18; (P) t , (P) k , (P)„ , (P) kl , (V) d and (Z) c are oligonucleotides preferably including at least one position that is not deoxynucleotide (e.g. 2'-H containing nucleotide); each (P) t ,(P) k , (P) tl , (P) kl , (V) d and (Z) c may include phosphodiester, phosphorothioate, phosphorodithioate, 5'-thiophosphate " , methylphosphonate linkers and the like or a combination thereof; k and t may be the 5 same length (k=t) or different lengths (k ≠ t); (M) w is an oligonucleotide sequence whose inter-nucleotide linkers may include phosphodiester, phosphorothioate, 5'thiophosphate, methylphosphonate, or phosphorodithioate linkers or a combination thereof; t, k, and w may be of the same length (k = t = w) or different length (k ≠ t ≠ w) or (k = t ≠ w) or (k ≠ t = w) or (k = w ≠ t); at least one or more of each said (P)t, (P)k, i o and (M) w is an oligonucleotide of sufficient length to stably interact independently with a target sequence (the target can be an RNA, DNA or RNA DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5'-thiophosphate, 1 5 methylphosphonate or others known in the art). In a preferred embodiment N and/or N' in (N»N') 0 , F and/or F' in (F»F') h and/or (Z) c , may optionally be able to independently interact with a target sequence. Formula VI: where, each P, N, F, Z, and M represents independently a nucleotide which may be same or different; • indicates hydrogen bond formation between two adjacent nudeotides, N' is a nucleotide complementary to N; F' is a nucleotide complementary to F; o is an integer greater than or equal to 3, more specifically 4, 5, 6, 7, 9, 10, 11, 12, 5 or 15; k is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; kl is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; t is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; tl i o is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; w is an integer greater than or equal to 4 and preferably less than 100, more specifically 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; h is an integer greater than or equal to 2 and preferably less than about 10, more specifically 2, 3, 4, 5, 6, 7, 8, or 9; c is an integer greater than or equal to 0 and 1 5 preferably less than about 20, more specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, or 18; (P) t ,(P) k , and (Z) c is an oligonucleotide preferably including at least one position that is not deoxynucleotide (e.g. 2'-H containing nucleotide); each (P) t ,(P) k , and (Z) c may include phosphodiester, phosphorothioate, phosphorodithioate, 5'-thiophosphate, methylphosphonate linkers and the like or a combination thereof; k and t may be the θ same length (k=t) or different lengths (k ≠ t); kl and tl may be the same length (kl=tl) or different lengths (kl ≠ tl); (M) w is an oligonucleotide sequence whose inter- nucleotide linkers may include phosphodiester, phosphorothioate, 5'thiophosphate, methylphosphonate or phosphorodithioate linkers or a combination thereof; t, k, and w may be of the same length (k = t = w) or different length (k ≠ t ≠ w) or (k = t ≠ w) or (k 25 ≠ t = w) or (k = w ≠ t); tl, kl, and w may be of the same length (kl = tl= w) or different length (kl ≠tl ≠w) or (kl = tl ≠ w) or (kl ≠ tl = w) or (kl = w ≠ tl); at least one or more of each said (P)„ (P) k , (P) tl , (P) kl ,and (M) w is an oligonucleotide of sufficient length to stably interact independently with a target sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage; phosphorothioate, phosphorodithioate or others known in the art). In a preferred embodiment N and/or N' in (N«N') 0 , F and/or F' in (F»F') h and/or (Z) c , may optionally be able to independently interact with a target sequence. Formula VII: where, each P, N, F, V, Z, and M represents independently a nucleotide which i o may be same or different; • indicates hydrogen bond formation between two adjacent nudeotides, N' is a nucleotide complementary to N; F' is a nucleotide complementary to F; o is an integer greater than or equal to 3, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, or 15; k is zero or an integer greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; t is zero or an integer 15 greater than or equal to 3 and preferably less than about 100, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20; w is an integer greater than or equal to 4 and preferably less than 100, more specifically 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; d is an integer greater than or equal to 3 and preferably less than about 20, more specifically 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, or 18; h is an integer greater than or equal to 2 and preferably less than about 10, more specifically 2, 3, 4, 5, 6, 7, 8, or 9; c is an integer greater than or equal to 0 and preferably less than about 20, more specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, or 18; (P) t ,(P) k , (V) d and (Z) c are oligonucleotides preferably including at least one position that is not deoxynucleotide (e.g. 2'-H containing nucleotide); each 5 (P) t ,(P) k , (V) d and (Z) c may include phosphodiester, phosphorothioate, phosphorodithioate, 5'-thiophosphate, methylphosphonate linkers and the like or a combination thereof; k and t may be the same length (k=t) or different lengths (k ≠t); (M) w is an oligonucleotide sequence whose inter-nucleotide linkers may include phosphodiester, phosphorothioate, 5'thiophosphate, methylphosphonate, or i o phosphorodithioate linkers or a combination thereof; t, k, and w may be of the same length (k = t = w) or different length (k ≠ t ≠ w) or (k = t ≠ w) or (k ≠ t = w) or (k = w ≠ t); at least one or more of each said (P)t, (P)k, and (M) w is an oligonucleotide of sufficient length to stably interact independently with a target sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently 1 5 represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5'-thiophosphate, methylphosphonate or others known in the art). In a preferred embodiment N and/or N' in (N » N') 0 , F and/or F' in (F*F') h and/or (Z) c , may optionally be able to independently interact with a target θ sequence. Formula VIII: B B' I F I D « 0 I I κ « τ \ / w Where, each F, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, 5'-thiophosphate, phosphorodithioate, methylphosphonate linkers and the like or a combination thereof; F 5 and D independently or in combination form RNaseH-activating domain, wherein F and D are of length greater than or equal to 4 nudeotides if they form independent RNaseH domains and are of length greater than or equal to 2 nudeotides if they form RNaseH domain in combination; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is i o complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, 1 5 more specifically K and T form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the K»T and O*D base-paired regions may be contiguous or non-contiguous to each other; K, T, O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; F, D, K, T, W and O together are of sufficient length to stably interact with a target nucleic acid θ sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, 5'-thiophosphate, phosphorodithioate, methylphosphonate or others known in the art). 5 Formula IX: B B' 1 F / :> « • 0 1 1 κ « • T \ / w Where, each F, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, 5'-thiophosphate, 5 phosphorodithioate, methylphosphonate linkers and the like or a combination thereof; F and D independently form RNaseH-activating domain, wherein F and D are of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide i o sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater than or equal to two base pairs with each other that are contiguous or noncontiguous, more specifically K and T form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the 15 K«T and O»D base-paired regions may be contiguous or non-contiguous to each other; K, T, O, and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; F, D, K, T, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed 0 polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, 5'-thiophosphate, phosphorothioate, phosphorodithioate, methylphosphonate or others known in the art). Formula X: ~ B B' I F I 0 « D I I κ « τ \ / w 5 Where, each F, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, 5'-thiophosphate, phosphorodithioate, methylphosphonate linkers and the like or a combination thereof; F and D independently form RNaseH-activating domain, wherein F and D are of length i o greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, 15 more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater than or equal to two base pairs with each other that are contiguous or noncontiguous, more specifically K and T form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the K»T and O»D base-paired regions may be contiguous or non-contiguous to each other; K, T, O, and W are of length greater than or equal to 3 nudeotides and preferably less 20 than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; F, D, K, T, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5^ thiophosphate, methylphosphonate or others known in the art). 5 Formula XI: B B' I F / O - D I I K - T \ / w Where, each F, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different I O length and may include phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, methylphosphonate linkers and the like or a combination thereof; F and D independently or in combination form RNaseH-activating domain, wherein F and D are of length greater than or equal to 4 nudeotides if they form independent RNaseH domains and are of length greater than or equal to 2 nudeotides if they form 1 5 RNaseH domain in combination; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more θ specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically K and T form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the K»T and O«D base-paired regions may be contiguous or non-contiguous to each other; K, T, O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; F, D, KT, T, W and O together are of sufficient length to stably interact with a target nucleic acid 5 sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, methylphosphonate or others known in the art). i o Formula XII: B B' \ / W Where, each D, O and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and 1 5 may include phosphodiester, phosphorothioate, phosphorodithioate, methylphosphonate linkers and the like or a combination thereof; D independently forms an RNaseH- activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; 2o D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; D, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, methylphosphonate or others known in the art). Formula XIII: B B' 0 * D \ / W Where, each D, O and W represents independently an oligonucleotide whose i o nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate linkers and the like or a combination thereof; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an i s oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 20 8, 9, 10, 11, 12, 13, 14, 15, or 20; D, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate or others known in the art). Formula XIV: B B' I A I O ' D I I K - T \ / 5 w Where, each A, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, methylphosphonate linkers and the like or a combination thereof; i o D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs 15 with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically K and T form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the K*T and O«D base-paired regions may be contiguous or non-contiguous to each other; A, K, T, O and W are of length o greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; A, D, K, T, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage; phosphorothioate, 5 '-thiophosphate, phosphorodithioate, methylphosphonate or others known in the art). Formula XV: B B' I A / 0 « D I I κ « τ \ / w Where, each A, D, O, K, W and T represents independently an oligonucleotide i o whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, methylphosphonate linkers and the like or a combination thereof; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides 15 within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater than or equal to two base 2θ pairs with each other that are contiguous or non-contiguous, more specifically K and T form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the K*T and O«D base-paired regions may be contiguous or non-contiguous to each other; A, K, T, O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; A, D, K, T, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, methylphosphonate or others known in the art). Formula XVI: I O B B' I A I D - 0 i i \ / w Where, each A, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, 5 '-thiophosphate, 1 5 phosphorodithioate, methylphosphonate linkers and the like or a combination thereof; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary 2o to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically K and T form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the K*T and O*D base-paired regions may be contiguous or non-contiguous to each other; A, K, T, O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; A, D, K, T, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, ι o phosphorothioate, phosphorodithioate, methylphosphonate5' -thiophosphate, or others known in the art). Formula XVII: B B' I A / D - 0 I I κ * τ \ / w 15 Where, each A, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, methylphosphonate linkers and the like or a combination thereof; D independently forms an RNaseH-activating domain of length greater than or equal to 2o 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically K and T 5 form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the K*T and O»D base-paired regions may be contiguous or non-contiguous to each other; A, K, T, O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; A, D, K, T, W and O together are of sufficient length to stably interact with a target nucleic acid sequence t o (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, methylphosphonate or others known in the art). 1 5 Formula XVIII: B B' I A I < > W Where, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and 20 may include phosphodiester, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate linkers and the like or a combination thereof; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; A, O and W are of length greater than or equal to 3 5 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; A, D, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical I O linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate or others known in the art). Formula XIX: B B' I A I O - D < > W 1 5 Where, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate linkers and the like or a combination thereof; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • θ indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; A, O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; A, D, W and O together are of sufficient length to" stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate or others known in the art). Formula XX: I O B B' I F I 0 « D < > W Where, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, i s and/or methylphosphonate linkers and the like or a combination thereof; F and D independently form RNaseH-activating domains of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with 2o each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; F, D, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, 5'- thiophosphate, phosphorodithioate, methylphosphonate or others known in the art). Formula XXI: B B' | 1 F I 1 O • D \ < / \ M Where, each F, D, O, and W represents independently an oligonucleotide whose i o nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate linkers and the like or a combination thereof; F and D independently or in combination form RNaseH-activating domain, wherein F and D are of length greater than or equal to 4 nudeotides if they form independent RNaseH i 5 domains and are of length greater than or equal to 2 nudeotides if they form RNaseH domain in combination; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal o to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically K and T form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the K*T and O*D base-paired regions may be contiguous or non-contiguous to each other; O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; F, D, W and " O together are of sufficient length to stably interact with a target nucleic acid sequence 5 (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate or others known in the art). i o Formula XXII: B 3' 1 A D • O / \ \ W Where, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and 1 5 may include phosphodiester, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate linkers and the like or a combination thereof; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the 2θ nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; A, O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; A, D, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate or others known in the art). Formula XXIII: B B' I 1 A 1 I D • O \ < / \ i/V i o Where, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate linkers and the like or a combination thereof; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • i s indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; A, O and W are of length greater than or equal to 3 0 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; A, D, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, 5'-thiophosphate,amide linkage, phosphorothioate, phosphorodithioate, methylphosphonate or others known in the art). " Formula XXIV: 5 B B' I F I D » 0 < > W Where, each F, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, I O methylphosphonate linkers and the like or a combination thereof; F and D independently or in combination form RNaseH-activating domain, wherein F and D are of length greater than or equal to 4 nudeotides if they form independent RNaseH domains and are of length greater than or equal to 2 nudeotides if they form RNaseH domain in combination; • indicates hydrogen bond formation between two adjacent 1 5 nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; K and T form greater 0 than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically K and T form 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; the K»T and O«D base-paired regions may be contiguous or non-contiguous to each other; O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; F, D, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B * independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, 5'- thiophosphate, amide linkage, phosphorothioate, phosphorodithioate, methylphosphonate or others known in the art). Formula XXV: B B' I D - O < > ι o W Where, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and may include phosphodiester, phosphorothioate, phosphorodithioate, 5 '-thiophosphate, methylphosphonate linkers and the like or a combination thereof; F and D 1 5 independently form RNaseH-activating domains of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within an oligonucleotide; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous, more specifically D and O form 2, 3, θ 4, 5, 6, 7, 8, 9, 10 or 11 base pairs; O and W are of length greater than or equal to 3 nudeotides and preferably less than about 100 nudeotides, more specifically 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20; F, D, W and O together are of sufficient length to stably interact with a target nucleic acid sequence (the target can be an RNA, DNA or RNA/DNA mixed polymers); each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage (e.g. a phosphate ester linkage, amide linkage, phosphorothioate", phosphorodithioate, 5 '-thiophosphate, methylphosphonate or others known in the art). 5 In a preferred embodiment, the invention features an HPH molecule of any of formulae I-III, and V-VII, where the (M) w optionally includes an RNase H-activating region. By "RNase H-activating region" or "RNase H-activating Region" is meant, a region (generally greater than or equal to 4 nudeotides long, preferably 5, 6, 7, 8, 9, 10 i o or 11 nudeotides) of a nucleic acid molecule capable of binding to a target RNA to form, for example, a (M) w »target RNA complex that is recognized by cellular RNase H enzyme, where the RNase H enzyme will then bind to the (M) w » target RNA complex and cleave the target sequence. The RNase H-activating region comprises, phosphodiester, phosphorothioate (preferably four of the nudeotides are 1 5 phosphorothiote substitutions; more specifically, either 4, 5, 6, 7, 8, 9, 10, or 11 of the nudeotides are phosphorothiote substitutions), phosphorodithioate, 5 '-thiophosphate, or methylphosphonate backbone chemistry or a combination thereof. In addition to one or more backbone chemistries described above, the RNase H-activating region comprises deoxyribose, arabino, fluoroarabino or a combination thereof, nucleotide 2o sugar chemistry. Those skilled in the art will recognize that the foregoing are non- limiting examples and that any combination of phosphate, sugar and base chemistry of a nucleic acid that supports the activity of RNase H enzyme is within the scope of the definition of the RNase H-activating region and the instant invention. By "nucleotide" as used herein is as recognized in the art to include natural bases 25 (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleotide sugar moiety. Nudeotides generally comprise a base, sugar and a phosphate group. The nudeotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nudeotides, non-natural nudeotides, non-standard nudeotides and other; see for example, Usman and McSwiggen, supra; Eckstein et al, International PCT Publication No. WO 92/07065; Usman et al, International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra) all of which are hereby incorporated by 5 reference herein). Examples of modified nucleic acid bases are known in the art and have recently been summarized by Limbach et al, 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of base modifications that can be introduced into nucleic acid molecules include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3 -methyl uracil, dihydrouridine, naphthyl, I O aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6- alkylpyrimidines (e.g. 6-methyluridine), propyne, and others (Burgin et al, 1996, Biochemistry, 35, 14090; Uhlman & Peyman, supra). By "modified bases" in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1' 1 5 position or their equivalents; such bases may be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate- binding regions of the nucleic acid molecule. By "ribonucleotide" is meant a nucleotide with one of the bases adenine, cytosine, guanine, or uracil joined to the 1' carbon of β-D-ribo-furanose. θ By "unmodified nucleotide" is meant a nucleotide with one of the bases adenine, cytosine, guanine, thymine, uracil joined to the 1' carbon of β-D-ribo-furanose. By "modified nucleotide" is meant a nucleotide that contains a modification in the chemical structure of an unmodified nucleotide base, sugar and/or phosphate. By "abasic" is meant nucleic acid sugar moieties lacking a base or having other 25 chemical groups in place of base at the 1' position. By "sufficient length" is generally meant an oligonucleotide of greater than or equal to 4 nudeotides, or an equivalent chemical moiety able to bind and interact with a target nucleic acid molecule in solution and/or in a cell under physiological condition ' s " . By "complementarity" is meant that a nucleic acid can form hydrogen bond(s) 5 with another RNA sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., ribozyme cleavage, antisense or triple helix inhibition. Determination of binding free energies for I O nucleic acid molecules is well known in the art (see, e.g., Turner et al., 1987, CSH Symp. Quant. Biol. LII pp.123-133; Frier et al., 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc. 109:3783-3785. A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a i 5 second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary). "Perfectly complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. By "stably interact" is meant an interaction of the oligonucleotides with target 20 nucleic acid (e.g., by forming hydrogen bonds with complementary nudeotides in the target under physiological conditions). The term shall also mean the interaction of HPH molecules with the target molecule for a duration, under physiological conditions, in solution or in a cell, sufficient for the HPH molecule to interfere with the function of the target nucleic acid molecule. 25 Typically, antisense molecules will be complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule may bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule may bind such that the antisense molecule forms a loop. Thus, the antisense molecule may be complementary to two (ό even more) non-contiguous substrate sequences or two (or even more) non-contiguous 5 sequence portions of an antisense molecule may be complementary to a target sequence or both. By "nucleic acid molecule" as used herein is meant a molecule comprising nudeotides. The nucleic acid can be composed of modified or unmodified nudeotides or non-nucleotides or various mixtures and combinations thereof. i o By "inhibit" it is meant that the activity of target genes or level of mRNAs or equivalent RNAs encoding target genes is reduced below that observed in the absence of the nucleic acid molecule of the invention. In one embodiment, inhibition with HPH molecules preferably is below that level observed in the presence of an mismatched nucleic acid molecule that is not able to stably bind to the same site on the mRNA. In 1 5 another embodiment, inhibition with HPH nucleic acid molecules, is preferably greater than that observed in the presence of for example, an oligonucleotide with scrambled sequence or with mismatches. In another embodiment, inhibition of target genes with the nucleic acid molecule of the instant invention is greater than in the presence of the nucleic acid molecule than in its absence. By "inhibit" is also meant, an impediment to θ normal function of a macromolecule caused by the introduction a foreign substance, such as the HPH molecule. By "target sequence" or "target nucleic acid molecule" is meant, a gene or partial sequence thereof, and those elements necessary for its expression, regulation, or its transcription or replication product or intermediates or portions thereof, including 25 DNA, RNA or protein.. Non-limiting examples of target sequence include c-raf mRNA, hepatitis C RNA, vascular endothelial growth factor receptor (e.g., fit- and KDR), ras RNA, and the like. By "gene" it is meant a nucleic acid that encodes an RNA. By "antisense" is meant a nucleic acid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-PNA (protein nucleic acid; Egholm et al, 5 1993 Nature 365, 566) interactions and alters the activity of the target RNA (for a review see Stein and Cheng, 1993 Science 261, 1004). By "equivalent" RNA to target genes is meant to include those naturally occurring RNA molecules having homology (partial or complete) to genes or encoding for proteins with similar function as genes in various animals, including human, rodent, i o primate, rabbit and pig. The equivalent RNA sequence also includes in addition to the coding region, regions such as 5 '-untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like. By "related" is meant that the inhibition of target gene RNAs and thus reduction in the respective levels of protein activity will relieve to some extent the symptoms of 1 5 the disease or condition. By "cap structure" is meant chemical modifications which have been incorporated at the terminus of the oligonucleotide (e.g., B and B' in formulae above). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and may help in delivery and/or localization within a cell. 2θ In another preferred embodiment, (P) k> (P)„ (N'N') 0 , (F » F (V) d , (Z) c (P) kl> (P) tl , (M) w , (Y) r , (Y) f , D, K, T, W and/or E independently include modifications selected from a group comprising 2'-Oalkyl (e.g. 2'-O-allyl; Sproat et al, supra) sometimes referred to as RNA modifications; 2'-O-alkylthioalkyl (e.g. 2'-0-methylthiomethyl; Karpeisky et al, 1998, Nucleosides & Nudeotides 16, 955-958); L-nucleotides 25 (Tazawa et al, 1970, Biochemistry 3499; Ashley, 1992, J. Am. Chem. Soc. 114, 9731; Klubmann et al, 1996, Nature Biotech 14, 1112); 2'-C-alkyl (Beigelman et al, 1995, J. Biol. Chem. 270, 25702); 1-5-Anhydrohexitol; 2,6-diaminopurine (Strobel et al, 1994, Biochem. 33, 13824-13835); 2'-(N-alanyl) amino-2' -deoxynucleotide; 2'-(N-beta^ alanyl) amino; 2'-deoxy-2'-(lysyl) amino; 2'-O-amino (Karpeisky et al, 1995, 5 Tetrahedron Lett. 39, 1131); 2'-deoxy-2'-(N-histidyl) amino; 5-methyl (Strobel, supra); 2'-(N-b-carboxamidine-beta-alanyl) amino; 2'-deoxy-2'-(Ν-beta-aianyl) (Matulic- Adamic et al, 1995, Bioorg. & Med. Chem. Lett. 5,2721-2724); xylofuranosyl (Rosemeyer et al, 1991, Helvetica Chem. Ada, 74, 748; Seda et al, 1994, Helvetica Chem. Acta, 77, 883; Seela et α/., 1996, Helvetica Chem. Acta, 79, 1451). I O In yet another preferred embodiment, B' is selected from a group comprising inverted abasic residue,. 4',5'-methylene nucleotide; l-(beta-D-erythrofuranosyl) nucleotide, 4'-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L- nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; tΛreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; acyclic 3,4- 1 5 dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide, 3'-3'-inverted nucleotide moiety; 3 '-3 '-inverted abasic moiety; 3'-2'-inverted nucleotide moiety; 3'-2'- inverted abasic moiety; 1 ,4-butanediol phosphate; 3'-phosphoramidate; hexylphosphate; aminohexyl phosphate; 3'-phosphate, phosphorothioate (preferably three of the terminal nudeotides are phosphorothiote substitutions; more specifically, either 1, 2, 3, 4 or 5 of 2θ the terminal nudeotides are phosphorothiote substitutions); phosphorodithioate; or bridging or non-bridging methylphosphonate moiety (for more details see Beigelman et al, International PCT publication No. WO 97/26270, incorporated by reference herein). In yet another preferred embodiment, B is selected from a group comprising, 4',5'-methylene nucleotide; l-(beta-D-erythrofuranosyl) nucleotide; 4'-thio nucleotide, 25 carbocyclic nucleotide; 5'-amino-alkyl phosphate; l,3-diamino-2-propyl phosphate, 3- aminopropyl phosphate; 6-aminohexyl phosphate; 1 ,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha- nucleotide; modified base nucleotide; phosphorodithioate; t/zreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5- dihydroxypentyl nucleotide, 5'-5'-inverted nucleotide moeity; 5'-5'-inverted abasic moeity; 5'-phosphoramidate; 5'-phosphorothioate; 1 ,4-butanediol phosphate; 5'-amino; 5 bridging and/or non-bridging 5'-phosphoramidate, phosphorothioate (preferably three of the terminal nudeotides are phosphorothiote substitutions; more specifically, either 1, 2, 3, 4 or 5 of the terminal nudeotides are phosphorothiote substitutions); and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5'-mercapto moieties (for more details see Beaucage and Iyer, 1993, Tetrahedron 49, 1925; i o incorporated by reference herein). An "alkyl" group refers to a saturated aliphatic hydrocarbon, including straight- chain, branched-chain, and cyclic alkyl groups. Preferably, the alkyl group has 1 to 12 carbons. More preferably it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkyl group may be substituted or unsubstituted. When substituted 1 5 the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, =O, =S, NO2 or N(CH3)2, amino, or SH. The term also includes alkenyl groups which are unsaturated hydrocarbon groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, more 20 preferably 1 to 4 carbons. The alkenyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, =O, =S, NO2, halogen, N(CH3)2, amino, or SH. The term "alkyl" also includes alkynyl groups which have an unsaturated hydrocarbon group containing at least one carbon- carbon triple bond, including straight-chain, branched-chain, and cyclic groups. 25 Preferably, the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkynyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, =O, =S, NO2 or N(CH3)2, amino or SH. Such alkyl groups may also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups. An "aryl" group refers to an aromatic group which has at least one ring having a conjugated p electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. The preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups. An "alkylaryl" group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above. Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted. Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted. An "amide" refers to an -C(O)-NH-R, where R is either alkyl, aryl, alkylaryl or hydrogen. An "ester" refers to an -C(O)-OR', where R is either alkyl, aryl, alkylaryl or hydrogen. In a preferred embodiment, the HPH molecules including the molecules described in formulae I-XXV are capable of binding to the target nucleic acid molecules in a sequence-specific manner. The stable interaction between the HPH molecule and the target molecules interferes with the normal function of the target molecule. Such interaction, for example, may cause inhibition of the function of the target molecule, such as transcription, translation, and replication. The HPH molecules of the invention interact and interfere with the target molecule in vitro or in vivo in a bacterial cell, microbial system, plant system, or mammalian system to modulate the function of the target molecule in such biological systems. In a preferred embodiment, the HPH molecules of the instant invention are used to inhibit target-gene expression in a biological system, more specifically in a cell, tissue, organ, and animal. In a preferred embodiment, the HPH nucleic acid molecules including the molecules of formulae I-III and V-XXV comprise at least one phosphate backbone modification, where such a modification is phosphorothioate (preferably four of the 5 nudeotides have phosphorothiote substitutions; more specifically, either 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 19, 21, 23 or 25 of the nudeotides have phosphorothiote substitutions), phosphorodithioate, 5 '-thiophosphate, or methylphosphonate backbone chemistry or a combination thereof. In a preferred embodiment, the HPH nucleic acid molecules including the i o molecules of formulae I-XXV are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells. The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through injection, infusion pump or stent, with or without their incoφoration in biopolymers. 1 5 In another aspect of the invention, the HPH nucleic acid molecules described in formulae IV are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. HPH molecule expressing viral vectors could be constructed based on, but not limited to, adeno- associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant θ vectors capable of expressing the HPH molecules are delivered as described above, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of HPH nucleic acid molecules. Such vectors might be repeatedly administered as necessary. Once expressed, the nucleic acid molecules bind to target mRNA. Delivery of nucleic acid molecules expressing vectors could be systemic, such 5 as by intravenous or intramuscular administration, by administration to target cells ex- planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review see Couture and Stinchcomb, 1996, TIG., 12, 510). In another aspect of the invention, nucleic acid molecules that bind target molecules and inhibit cell proliferation are expressed from transcription units inserted into DNA, RNA, or viral vectors. 5 Preferably, the recombinant vectors capable of expressing the HPH molecules are locally delivered as described above, and transiently persist in smooth muscle cells. However, other mammalian cell vectors that direct the expression of RNA may be used for this purpose. By "phenotype" is meant, the entire physical, biochemical, and physiological i o makeup of an organism as determined both genetically or environmentally and any one or any group of such traits. In a preferred embodiment, the 5' and/or 3' portions of the hairpin region of the HPH molecule is independently complementary to the target sequence. Specifically, N and/or N' portion of the (N»N') 0 in formulae I- VII is independently complementary to 1 5 the target sequence. In a preferred embodiment, the 5' and/or 3' portions of the hairpin region of the HPH molecule is independently complementary to the target sequence. Specifically, N and/or N' portion or the (F»F') h in formulae I- VII is independently complementary to the target sequence. θ In a preferred embodiment, the invention features a method of modulating the function of a target sequence including the steps of contacting the target sequence with the HPH molecules, including the molecules of formulae I-XXV, under conditions suitable for the modulation of the function of the target sequence. Such modulation can take place in vitro or in vivo, in microbial, plant, or mammalian systems where the 5 modulation of function may include inhibition of gene expression, modification of cellular function, change in the organism's phenotype, inhibition of replication of a virus and/or viral RNA, inhibition of motility, migration of a cell and others. By "patient" is meant an organism that is a donor or recipient of explanted cells or the cells themselves. "Patient" also refers to an organism to which enzymatic nucleic 5 acid molecules can be administered. Preferably, a patient is a mammal or mammalian cells. More preferably, a patient is a human or human cells. By "vectors" is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid. In another aspect, the nucleic acid molecule of the present invention is i o administered individually or in combination or in conjunction with other drugs, and can be used to treat diseases or conditions. For example, to treat a disease or condition associated with cancer, the patient may be treated, or other appropriate cells may be treated, as is evident to those skilled in the art. By "comprising" is meant including, but not limited to, whatever follows the i s word "comprising". Thus, use of the term "comprising" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present. By "consisting of is meant including, and limited to, whatever follows the phrase "consisting of. Thus, the phrase "consisting of indicates that the listed elements are required or mandatory, and that no other elements may be present. o By "consisting essentially of is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or 5 not they affect the activity or action of the listed elements. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Description Of The Preferred Embodiments The drawings will first briefly be described. 5 Drawings: Figure 1 is a schematic representation of the binding of the hairpin hybridizer (HPH) molecule to a target RNA. During binding, both the 5' and 3' sequences of the hairpin region may be non-complementary to the target sequence. Alternatively, either the 5' or 3' sequence may be complementary to the target RNA molecule i o independently. Figure 2A displays the hairpin structure of the unbound HPH nucleic acid molecule including a 4 base pair stem and an internal 9-nucleotide DNA sequence. The figure further displays the structure of the nucleic acid molecule before and after binding to RNA. This molecule's 5' and 3' sequences form the hairpin structure but do 1 5 not base pair with the target RNA molecule. Figure 2B displays the hairpin structure of the unbound nucleic acid molecule also including a 4-base-pair stem and an internal 9- nucleotide DNA sequence. This molecule's 5' and 3' sequence forms the hairpin structure. In certain embodiments, the 5' and/or 3' sequence is capable of binding to the target RNA molecule independently. θ Figure 3 displays non-limiting structures of the HPH molecules that are within the scope of the present invention. In Figure 3 A, (1) represents a circular nucleic acid molecule with an internal base-paired hairpin stem structure, each loop within the molecule comprises an RNase H-activating Region and a Non-RNase H-activating Region and is capable of binding to a Target Sequence; (2) represents a molecule 25 comprising an RNase H-activating Region and a Non-RNase H-activating Region capable of interacting with the Target Sequence and includes an internal base-paired haiφin stem region and additional nucleotide sequences at the 5' and 3' ends of the haiφin structure which are of equal or dissimilar lengths that may optionally bind to Target Sequences; (3) represents a molecule comprises an RNase H-activating Region 5 and a Non-RNase H-activating Region capable of interacting with the Target Sequence and an internal base-paired haiφin stem region and additional nucleotide sequence at the 5' end of the haiφin stem structure which may optionally bind to Target Sequence; (4) represents a molecule comprising an RNase H-activating Region and a Non-RNase H-activating Region capable of interacting with the Target Sequence and an internal i o base-paired haiφin stem region and additional nucleotide sequences at the 3' end of the haiφin structure that may optionally bind to target sequence; (5) represents a molecule comprises an RNase H-activating Region and a Non-RNase H-activating Region capable of interacting with the Target Sequence and an internal haiφin stem region and additional nucleotide sequences at the 5' and 3' ends of the haiφin structure which are 1 5 asymmetric in length and which may optionally bind to Target Sequences; (6) represents a discontinuous circular nucleic acid molecule comprising an RNase H- activating Region and a Non-RNase H-activating Region capable of interacting with the Target Sequence and an internal haiφin stem structure, each loop at the 3' and the 5' ends of the haiφin region is independently capable of binding to a target sequence. In θ Figure 3B, (1) represents a HPH nucleic acid molecule structure, where the RNase H- activating Region is at the 5' end of the molecule and a portion of the RNase H- activating Region forms a haiφin stem structure with a portion of the 3' region of the HPH molecule. Both the RNase H-activating Region and the Non-RNase H-activating Regions are independently or in combination are capable of interacting with the Target 25 sequence in a sequence-specific manner; (2) and (5) represents a HPH nucleic acid molecule structure, where a portion of the RNase H-activating Region forms a haiφin stem structure with a portion of the non-RNaseH-activating region of the HPH molecule. Both the RNase H-activating Region and the Non-RNase H-activating Regions are independently or in combination are capable of interacting with the Target sequence in a sequence-specific manner; (3) and (6) represent a HPH nucleic acid molecule structure, where the a portion of the RNase H-activating Region and a portion of the Non-RNase H-activating region forms a haiφin stem structure with a portion of 5 the Non-RNase H-activating region located in a different part of the HPH molecule. Both the RNase H-activating Region and the Non-RNase H-activating Regions are independently or in combination are capable of interacting with the Target sequence in a sequence-specific manner; (4) represents a HPH nucleic acid molecule structure, where the RNase H-activating Region is at the 3' end of the molecule and a portion of i o the RNase H-activating Region forms a haiφin stem structure with a portion of the 5' region of the HPH molecule. Both the RNase H-activating Region and the Non-RNase H-activating Regions are independently or in combination are capable of interacting with the Target sequence in a sequence-specific manner. In Figure 3C, (1) and (3) represents a HPH nucleic acid molecule structure, where a portion of the RNase H- 1 5 activating Region forms a haiφin stem structure with a portion of the non-RNaseH- activating region of the HPH molecule. Both the RNase H-activating Region and the Non-RNase H-activating Regions are independently or in combination are capable of interacting with the Target sequence in a sequence-specific manner; (2) and (4) represents a HPH nucleic acid molecule structure, where the a portion of the RNase H- θ activating Region and a portion of the Non-RNase H-activating region form a haiφin stem structure with a portion of the Non-RNase H-activating region located in a different part of the HPH molecule. Both the RNase H-activating Region and the Non- RNase H-activating Regions are independently or in combination are capable of interacting with the Target sequence in a sequence-specific manner. 5 Figure 4 displays a graph demonstrating the effect of a 31 mer HPH nucleic acid molecule of the present invention on reducing c-raf mRNA levels in PC-3 cells compared to untreated and mismatch controls. The cells were treated with nucleic acid molecules for 1, 3, or 5 days and then harvested to quantify the c-raf RNA. Figure 5 displays a graph demonstrating the effect of a 33mer nucleic acid molecule of the present invention on reducing c-raf mRNA levels in PC-3 cells compared to untreated and mismatch controls. The cells were treated with the HPH nucleic acid molecules for 1, 3, or 5 days and then harvested to quantify the c-raf RNA. 5 Figure 6 displays a graph demonstrating the effect of a 35mer HPH nucleic acid molecule of the present invention on reducing c-raf mRNA levels in PC-3 cells compared to untreated and mismatch controls. The cells were treated with nucleic acid molecules for 1, 3, or 5 days and then harvested to quantify the c-raf RNA. Figure 7 displays a graph demonstrating the effect of a 31 mer HPH nucleic acid I O molecule of the present invention on reducing c-raf mRNA levels in PC-3 cells compared to a mismatch control. Figure 8 displays a graph demonstrating the effect of a 31 mer HPH linear antisense molecule on reducing c-raf mRNA levels in PC-3 cells compared to a mismatch control. 15 Figure 9 displays the HPH nucleic acid molecule-based specific inhibition of c-raf RNA levels in PC-3 cells and the effect of 1, 2 and 4 base mismatches on this inhibition. Figure 10 displays several non-limiting examples of psuedoknot haiφin hybridizer molecules. Figure 10A is a psuedoknot haiφin hybridizer molecule θ comprised of 2 haiφin structures, and a target binding sequence located in closer proximity to the 5' end of the nucleic acid molecule compared to the 3' end. Figure 10B is a psuedoknot haiφin hybridizer molecule comprised of 2 haiφin structures, and a target binding sequence located in closer proximity to the 3' end of the nucleic acid molecule compared to the 5' end. Figure IOC is a psuedoknot haiφin hybridizer 25 molecule comprised of 2 haiφin structures, and two target binding sequences. Figure 10D is a psuedoknot haiφin hybridizer molecule comprised of 2 haiφin structures, a target binding sequence located in closer proximity to the 3' end of the nucleic acid molecule compared to the 5' end, and additional nucleotide sequences attached at the 5' and 3' ends of the haiφin hybridizer molecule. These additional sequences may be of equal or unequal length. Figure 10E is a psuedoknot haiφin hybridizer molecule comprised of 2 haiφin structures, 2 target binding sequences, and additional nucleotide sequences attached at the 5' and 3' ends of the haiφin hybridizer molecule. These 5 additional sequences may be of equal or unequal length. Figure 1 OF is a psuedoknot haiφin hybridizer molecule comprised of 2 haiφin structures, a target binding sequence located in closer proximity to the 5' end of the nucleic acid molecule compared to the 3' end, and an additional nucleotide sequence attached at the 5' of the haiφin hybridizer molecule. Figure 10G is a psuedoknot haiφin hybridizer molecule i o comprised of 2 haiφin structures, a target binding sequence located in closer proximity to the 5' end of the nucleic acid molecule compared to the 3' end, and additional nucleotide sequences attached at the 5' and 3' ends of the haiφin hybridizer molecule. These additional sequences may be of equal or unequal length. Figure 11 displays a graph demonstrating the effect of HPH nucleic acid molecule 1 5 of various configurations of the present invention on reducing c-raf mRNA levels in PC-3 cells compared to controls. Figure 12 displays a graph demonstrating the effect of a HPH nucleic acid molecule of the varying sizes and configurations of the present invention on reducing IMPDH II mRNA levels in PC-3 cells compared to untreated and mismatch controls. θ Figure 13 displays a graph demonstrating the effect of a HPH nucleic acid molecule of the varying sizes and configurations of the present invention on reducing IMPDH II mRNA levels in PC-3 at an oligonucleotide concentration of 100 nM. Mechanism of action of The HPH Nucleic Acid Molecules of the Invention 25 Antisense molecules known in the art are usually RNA or DNA oligonucleotides and primarily function by specifically binding to complementary (matching) sequences resulting in inhibition of peptide synthesis (Wu-Pong, Nov 1994, BioPharm, 20-33). The oligonucleotide binds to target RNA by Watson Crick base-pairing and blocks gene expression by preventing ribosomal translation of the bound sequences by either steric blocking or RNase H-mediated degradation of target RNA. Antisense molecules may also alter protein synthesis by interfering with RNA processing or transport from 5 the nucleus into the cytoplasm (Mukhopadhyay & Roth, 1996, Crit. Rev. in Oncogenesis 7, 151-190). In addition, binding of single stranded DNA to RNA may result in nuclease degradation of the heteroduplex (Wu-Pong, supra; Crooke, supra). To date, the only backbone-modified DNA chemistry which will act as substrates for RNase H are i o phosphorothioates and phosphorodithioates. Recently it has been reported that 2'- arabino and 2'-fluoro arabino- containing oligos can also activate RNase H activity. A number of antisense molecules have been described that utilize novel configurations of chemically modified nudeotides, secondary structure, and/or RNase H substrate domains (Woolf et al, International PCT Publication No. WO 98/13526; 1 5 Thompson et al, USSN 60/082,404 which was filed on April 20, 1998 both of which are incoφorated in their entirety by reference herein). The antisense molecules described in the art are essentially single-stranded linear oligonucleotides which are known to tolerate a number of mismatches and still form stable hybrids with a target sequence raising the concern of safety and toxicity in θ organisms. While these molecules are functional, for certain applications, including pharmaceutical compositions, greater specificity, lower toxicity and higher stability is desirable. The specificity of oligonucleotides described above may be increased by using the HPH nucleic acid molecule of the present invention which form internal haiφin 25 structure with hydrogen bond interactions. Partial complementarity of these HPH oligonucleotides with target sequences do not allow for efficient opening of the internal haiφin structure of the HPH oligonucleotide resulting in a competition between a haiφin structure and binding to target a sequence. Therefore, hybridization interaction between HPH and target sequences with one or more mismatched sequences, occurs inefficiently, thereby making them inefficient inhibitors of gene expression (see fig. 9).Tyagi & Kramer, 1996, Nat Biotechnol 14,303-308; Tyagi & Kramer, 1998, Nat 5 Biotechnol 16, 359-363 have shown that oligonucleotides such as molecular beacons which have a 10 base pair or more internal haiφin stems are capable of binding to a target sequence in a highly sequence specific manner in solution. The specific interaction of a haiφin DΝA with target RΝA was also demonstrated in cells (Kostrikis. et al, 1998 , Science 279, 1228-1229) where the haiφin DΝA was used to i o detect the presence of bFGF RΝA, these oligonucleotides however were not used to inhibit gene expression. In addition to the increased specificity, the intramolecular bonding of the haiφin hybridizer molecules can result in increased stability. Haiφin sequences located at the respective ends of the oligonucleotide may increase the stability of these 15 reagents because the lack of unpaired free nudeotides reduces the potential for degradation by exonucleases. End stabilization is currently conferred by chemical modifications (phosphorothioate linkage etc.) which may itself decrease specificity, and possibly increase cytotoxicity. The increased stability of haiφin-end vector-based ribozyme constructs has already been demonstrated (Thompson et al., 1995, Nucleic o Acids Research 23, 2259-2268). The effectiveness of these HPH molecules may be enhanced by the addition of nudeotides which act as substrates for RΝase H within the molecule. However, binding of DΝA to RΝA is not as thermodynamically favorable as an RΝA to RΝA interaction (Altmann et al., 1996, Chimia 50, 168-176). Therefore a molecule with both 25 RΝA and DΝA nudeotides may be able to bind efficiently as well as promote degradation of the RΝA molecule by RΝase H. Inoe & Ohtsuka, 1987, Nucleic Acids Research 115, 6131, first proposed an oligonucleotide with a central region consisting of oligodeoxynucleotides flanked by 2'-O-methyl modified nucleotide regions. The region of oligodeoxynucleotides in such a chimeric molecule is recognized by RNase H when bound to target RNA; and facilitates cleavage of target RNA by RNase H. (Inoe & Ohtsuka, 1987, EERS Lett. 215, 327; Shibahara & Morisava, 1987, Nucleic Acids Res. 15, 4403). These chimeric oligonucleotides were proposed to interact with target 5 RNA more stably than an all DNA oligonucleotide. Alternatively, the nucleic acid molecule may function by binding to the target molecule that results in steric hindrance for ribosomal translation. A number of chemical modifications may be utilized with this strategy including insertion of 2'-0-methyl modification at every nucleotide in the molecule. i o One of the most studied and utilized chemical alterations in oligonucleotides has been backbone modifications such as phosphorothioates, phosphorodithioates, and 5'thiophosphates. Phosphorothioate oligonucleotides are nucleic acid molecules whose phosphodiester linkage has been modified by substituting a sulfur atom in place of an oxygen atom. In addition to increased nuclease resistance, phosphorothioate, i s phosphorodithioate, and 5'thiophosphates oligonucleotides are substrates for ribonuclease H (RNase H) (Monia, supra; Crooke et al., 1995, Biochem. J. 3112, 599- 608). RNase H is an endonuclease which catalyzes the degradation of RNA in an RNA-DNA heteroduplex (Hostomsky et al., 1993 in Nucleases, Linn et al., eds., Cold Spring Harbor Laboratory Press, NY, 341-376). RNA/DNA heteroduplexes, called 0 Okazaki fragments, are formed naturally during DNA replication. Therefore, the normal function of RNase H is to degrade the RNA portion of the heteroduplex to complete DNA replication. In experiments with E. Coli RNase H, the phosphorothioate oligonucleotide activated the enzyme more efficiently (2-5 fold) compared to a standard phosphodiester containing oligonucleotide (Crooke, 1995, supra). 25 Synthesis of Nucleic acid Molecules Synthesis of nucleic acids greater than 100 nudeotides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive. In this invention, small nucleic acid motifs ("small refers to nucleic acid motifs no more than 5 100 nudeotides in length, preferably no more than 80 nudeotides in length, and most preferably no more than 40 nudeotides in length; e.g., HPH nucleic acid molecules) are used for exogenous delivery. The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA structure. The oligodeoxyribonucleotides molecules of the instant invention were chemically i o synthesized using standard protocols as described in Caruthers et al., 1992, Methods in Enzymology 211,3-19, which is incoφorated herein by reference. The method of synthesis used for normal RNA follows the procedure as described in Usman et al, 1987 J. Am. Chem. Soc, 109, 7845; Scaringe et al, 1990 Nucleic Acids Res., 18, 5433; and Wincott et al, 1995 Nucleic Acids Res. 23, 2677- 1 5 2684; Wincott et al, 1997, Methods Mol. Bio., 74, 59) and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5 '-end, and phosphoramidites at the 3'-end and can be readily used to synthesize 2'-0-alkyl- containing oligonucleotides. In a non-limiting example, small-scale synthesis was conducted on a 394 Applied Biosystems, Inc. synthesizer using a modified 2.5 μmol 2o scale protocol with a 5 min. coupling step for alkylsilyl protected nudeotides and 2.5 min. coupling step for 2'-0-methylated nudeotides. Table I outlines the amounts, and the contact times, of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, CA) with minimal modification to the cycle. A 15- 25 fold excess (31 μL of 0.1 M = 3.1 μmol) of phosphoramidite and a 38.7-fold excess of S-ethyl tetrazole (31 μL of 0.25 M = 7.75 μmol) relative to polymer-bound 5'-hydroxyl was used in each coupling cycle. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, were 97.5-99%). Other oligonucleotide synthesis reagents used with the 394 Applied Biosystems, Inc. synthesizer included detritylation solution with 3% TCA n methylene chloride (ABI); capping was performed with 16% N-methyl imidazole in 5 THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution was 16.9 mM I 2 , 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile was used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) was made up from the solid obtained from American International Chemical, Inc. i o Deprotection of the the oligonucleotides of the instant invention was performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer- bound trityl-on oligoribonucleotide was transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 °C for 10 min. After cooling to -20 °C, the supernatant was removed from the polymer support. The i 5 support was washed three times with 1.0 mL of EtOH:MeCΝ:H2O/3 : 1 : 1 , vortexed and the supernatant was then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, were dried to a white powder. The base deprotected oligoribonucleotide was resuspended in anhydrous TEA/HF/NMP solution (300 μL of a solution of 1.5 mL N-methylpyrrolidinone, 750 μL TEA and 1 mL TEA » 3HF to θ provide a 1.4 M HF concentration) and heated to 65 °C. After 1.5 h, the oligomer was quenched with 1.5 M NH 4 HCO 3 . Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide was transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO:l/l (0.8 mL) at 65 °C for 15 min. The 5 vial was brought to room temperature. TEA»3HF (0.1 mL) was added and the vial was heated at 65 °C for 15 min. The sample was cooled at -20 °C and then quenched with 1.5 M NH 4 HCO 3 . For purification of the trityl-on oligomers, the quenched NH 4 HCO3 solution was loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA * was detritylated with 0.5% TFA for 13 min. The cartridge was then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide was then eluted with 30% acetonitrile. Alternatively or in addition to the methods described herein, oligonucleotides of the instant inventions can be purified by other methods known in the art, for example, see Sproat et al, 1999, Nucleic Acids Res., 27, 1950). The average stepwise coupling yields were >98% (Wincott et al, 1995 Nucleic Acids Res. 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the example described above including but not limited to 96-well format, all that is important is the ratio of chemicals used in the reaction. Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example by ligation (Moore et al, 1992, Science 256, 9923; Draper et al, International PCT publication No. WO 93/23569; Shabarova et al, 1991, Nucleic Acids Research 19, 4247; Bellon et al, 1997, Nucleosides & Nudeotides, 16, 951; Bellon et al, 1997 Bioconjugate Chem. 8, 204). Administration of Nucleic Acid Molecules Methods for the delivery of nucleic acid molecules are described in Akhtar et al, 1992, Trends Cell Bio., 2, 139; and Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995 which are both incoφorated herein by reference. Sullivan et al, PCT WO 94/02595, further describes the general methods for delivery of enzymatic RNA molecules. These protocols may be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules may be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incoφoration into other vehicles, such as hydrogeis, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. For some 5 indications, nucleic acid molecules may be directly delivered ex vivo to cells or tissues with or without the aforementioned vehicles. Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of a catheter, infusion pump or stent. Other routes of delivery include, but are not limited to, intravascular, intramuscular, subcutaneous or joint injection, aerosol inhalation, oral (tablet or pill form), topical, systemic, ocular, i o intraperitoneal and/or intrathecal delivery. More detailed descriptions of nucleic-acid delivery and administration are provided in Sullivan et al, supra and Draper et al, PCT WO93/23569 which are incoφorated by reference herein. The molecules of the instant invention can be used as pharmaceutical agents. Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to 15 some extent, preferably all of the symptoms) of a disease state in a patient. The negatively charged polynucleotides of the invention can be administered (e.g., RNA, DNA or protein) and introduced into a patient by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for θ formation of liposomes can be followed. The compositions of the present invention may also be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions; suspensions for injectable administration; and the like. The present invention also includes pharmaceutically acceptable formulations of 25 the compounds described. These formulations include salts of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid. A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a 5 cell or patient, preferably a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation to reach a target cell (i.e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other i o factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect. By "systemic administration" is meant in vivo systemic absoφtion or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Administration routes which lead to systemic absoφtion include, without 1 5 limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes expose the desired negatively charged polymers, e.g., nucleic acids, to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the 2θ instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach may provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage 25 and lymphocyte immune recognition of abnormal cells, such as cancer cells. The invention also features the use of the composition comprising surface- modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long- circulating liposomes or stealth liposomes). These formulations offer an method for- increasing the accumulation of drugs in target tissues. This class of drug carriers resists 5 opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull. 1995, 43, 1005-1011). Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized- I O target tissues (Lasic et al, Science 1995, 267, 1275-1276; Oku et al, 1995, Biochim. Biophys. Acta, 1238, 86-90). The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al, J. Biol Chem. 1995, 42, 24864-24870; Choi et al, International PCT i s Publication No. WO 96/10391; Ansell et al, International PCT Publication No. WO 96/10390; Holland et al, International PCT Publication No. WO 96/10392; all of which are incoφorated by reference herein). Long-circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive o MPS tissues such as the liver and spleen. The present invention also includes compositions prepared for storage or administration which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, 25 for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985) hereby incoφorated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents may be provided. These include sodium benzoate, sorbic acid and esters of /j-hydroxybenzoic acid. In addition, antioxidants and suspending agents may be used. A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the 5 symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day i o of active ingredients is administered dependent upon potency of the negatively charged polymer. The nucleic acid molecules of the present invention may also be administered to a patient in combination with other therapeutic compounds to increase the overall therapeutic effect. The use of multiple compounds to treat an indication may increase 1 5 the beneficial effects while reducing the presence of side effects. Alternatively, certain of the nucleic acid molecules of the instant invention (e.g., formula IV) can be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985 Science 229, 345; McGarry and Lindquist, 1986 Proc. Natl. Acad. Sci. USA 83, 399; Scanlon et al, 1991, Proc. Natl Acad. Sci. USA, 88, 10591-5; Kashani- 2θ Sabet et al, 1992 Antisense Res. Dev., 2, 3-15; Dropulic et al, 1992 J Virol, 66, 1432- 41; Weerasinghe et al, 1991 J. Virol, 65, 5531-4; Ojwang et al, 1992 Proc. Natl. Acad. Sci. USA 89, 10802-6; Chen et al, 1992 Nucleic Acids Res., 20, 4581-9; Sarver et al, 1990 Science 247, 1222-1225; Thompson et al, 1995 Nucleic Acids Res. 23, 2259; Good et al, 1997, Gene Therapy, 4, 45; all of these references are hereby 25 incoφorated in their totality by reference herein). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a ribozyme (Draper et al, PCT WO 93/23569, and Sullivan et al, PCT WO 94/02595; Ohkawa et al, 1992 Nucleic Acids Symp. Ser., 27, 15-6; Taira et al, 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al, 1993 Nucleic Acids Res., 21, 5 3249-55; Chowrira et al, 1994 J. Biol Chem. 269, 25856; all of these references are hereby incoφorated in their totality by reference herein). In another aspect of the invention, RNA molecules of the present invention are preferably expressed from transcription units (see for example Couture et al, 1996, TIG., 12, 510) inserted into DNA or RNA vectors. The recombinant vectors are i o preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors could be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the nucleic acid molecules are delivered as described above, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of nucleic 1 5 acid molecules. Such vectors might be repeatedly administered as necessary. Once expressed, the nucleic acid molecule binds to the target mRNA. Delivery of nucleic acid molecule expressing vectors could be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for 2θ introduction into the desired target cell (for a review see Couture et al, 1996, TIG, 12, 510). In one aspect the invention features, an expression vector comprising nucleic acid sequence encoding at least one of the nucleic acid molecules of the instant invention is disclosed. The nucleic acid sequence encoding the nucleic acid molecule 25 of the instant invention is operable linked in a manner that allows expression of that nucleic acid molecule. In another aspect the invention features, an expression vector comprising: a transcription-initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription-termination region (e.g., eukaryotic pol I, II or III termination region); c) a ~ gene encoding at least one of the nucleic-acid catalysts of the instant invention; and 5 wherein said gene is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector may optionally include an open reading frame (ORF) for a protein operably linked on the 5' side or the 3'-side of the gene encoding the nucleic- acid catalyst of the invention; and/or an intron (intervening sequences). i o Transcription of the nucleic acid molecule sequences are driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters will be expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on the nature of the gene regulatory sequences (enhancers, silencers, etc.) i 5 present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy- Stein and Moss, 1990 Proc. Natl. Acad. Sci. USA, 87, 6743-7; Gao and Huang 1993 Nucleic Acids Res., 21, 2867-72; Lieber et al, 1993 Methods Enzymol, 217, 47-66; Zhou et al., 1990 Mol. Cell. Biol, 10, 4529-37). Several investigators have 2o demonstrated that nucleic acid molecules, such as ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992 Antisense Res. Dev., 2, 3-15; Ojwang et al., 1992 Proc. Natl. Acad. Sci. U S A, 89, 10802-6; Chen et al, 1992 Nucleic Acids Res., 20, 4581-9; Yu et al, 1993 Proc. Natl. Acad. Sci. US A, 90, 6340-4; L'Huillier et al, 1992 EMBO J. 11, 4411-8; Lisziewicz et al, 25 1993 Proc. Natl. Acad. Sci. U. S. A., 90, 8000-4; Thompson et al, 1995 Nucleic Acids Res. 23, 2259; Sullenger & Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al, supra; Couture and Stinchcomb, 1996, supra; Noonberg et al, 1994, Nucleic Acid Res ~ 22, 2830; Noonberg et al, US Patent No. 5,624,803; Good et al, 1997, Gene Ther. 4, 5 45; Beigelman et al, International PCT Publication No. WO 96/18736; all of these publications are incoφorated by reference herein. The above ribozyme-transcription units can be incoφorated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral i o or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra). In yet another aspect, the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the invention, in a manner which allows expression of that nucleic acid molecule. The expression vector comprises in one embodiment; a) a transcription-initiation region; b) 1 5 a transcription termination region; c) a gene encoding at least one said nucleic acid molecule; and wherein said gene is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In another preferred embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription-termination region; c) an open reading o frame; d) a gene encoding at least one said nucleic acid molecule, wherein said gene is operably linked to the 3'-end of said open reading frame; and wherein said gene is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. 25 In yet another embodiment, the expression vector comprises: a) a transcription- initiation region; b) a transcription-termination region; c) an intron; d) a gene encoding at least one said nucleic acid molecule; and wherein said gene is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In a further embodiment, the expression vector comprises: a) a transcription- initiation region; b) a transcription-termination region; c) an intron; d) an open reading 5 frame; e) a gene encoding at least one said nucleic acid molecule, wherein said gene is operably linked to the 3'-end of said open reading frame; and wherein said gene is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. i o Optimizing Nucleic Acid Molecule Activity Chemically synthesizing nucleic acid molecules with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases may increase their potency (see e.g., Eckstein et al, International Publication No. WO 92/07065; Perrault et al, 1990 Nature 344, 565; Pieken et al., 1991 Science 253, 314; Usman and i s Cedergren, 1992 Trends in Biochem. Sci. 17, 334; Usman et al, International Publication No. WO 93/15187; and Rossi et al, International Publication No. WO 91/03162; Sproat, US Patent No. 5,334,711; and Burgin et al, supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of the nucleic acid molecules herein). Modifications which enhance o their efficacy in cells, and removal of bases from nucleic acid molecules to shorten oligonucleotide synthesis times and reduce chemical requirements are desired. (All these publications are hereby incoφorated by reference herein). There are several examples in the art describing sugar, base and phosphate modifications that can be introduced into nucleic acid molecules with significant 25 enhancement in their nuclease stability and efficacy. For example, oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'-flouro, 2'-O-methyl, 2'- H, nucleotide base modifications (for a review see Usman and Cedergren, 1992 TIBS 17, 34; Usman et al, 1994 Nucleic Acids Symp. Ser. 31, 163; Burgin et al, 1996 Biochemistry 35, 14090). Sugar modifications of nucleic acid molecules have been 5 extensively described in the art (see Eckstein et al., International Publication PCT No. WO 92/07065; Perrault et al. Nature 1990, 344, 565-568; Pieken et al. Science 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci. 1992, 17, 334-339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, US Patent No. 5,334,711 and Beigelman et al, 1995 J. Biol. Chem. 270, 25702; Beigelman et al, i o International PCT publication No. WO 97/26270; Beigelman et al, US Patent No. 5,716,824; Usman et al, US patent No. 5,627,053; Woolf et al, International PCT Publication No. WO 98/13526; Thompson et al, USSN 60/082,404 which was filed on April 20, 1998; Kaφeisky et al, 1998 Tetrahedron Lett. 39, 1131; all of which are hereby incoφorated in their totality by reference herein). Such publications, which 1 5 describe general methods and strategies to determine the location of incoφoration of sugar, base and/or phosphate modifications and the like into ribozymes without inhibiting catalysis, are incoφorated by reference herein. In view of such teachings, similar modifications can be used as described herein to modify the HPH nucleic acid molecules of the instant invention. 0 While chemical modification of oligonucleotide intemucleotide linkages with phosphorothioate, phosphorothioate, and/or 5' -methylphosphonate linkages improves stability, too many of these modifications may cause increased toxicity. Therefore, when designing HPH molecules, the amount of these intemucleotide linkages should be minimized. The reduction in the concentration of these linkages should lower toxicity 25 resulting in increased efficacy and higher specificity of these HPH molecules. Nucleic acid molecules having chemical modifications which maintain or enhance activity are disclosed herein. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered. Therapeutic HPH molecules delivered exogenously must optimally be stable within cells until translation of the target RNA has beerr inhibited long enough to reduce the levels of the undesirable protein. This period of 5 time varies between hours to days depending upon the disease state. Clearly, nucleic acid molecules must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA and DNA (Wincott et al, 1995 Nucleic Acids Res. 23, 2677; Caruthers et al, 1992, Methods in Enzymology 211,3-19) incoφorated by reference herein) have expanded the i o ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above. Use of these HPH molecules will lead to better treatment of disease progression by affording the possibility of combination therapies (e.g., multiple HPH molecules targeted to different genes, HPH molecules coupled with known small-molecule 1 5 inhibitors, or intermittent treatment with combinations of HPH molecules (including different HPH motifs) and/or other chemical or biological molecules)). The treatment of patients with nucleic acid molecules may also include combinations of different types of nucleic acid molecules. Target Validation 2o One of the most challenging tasks in drug discovery is the choice of a therapeutic target. Historically, traditional biochemical and other studies have offered limited information in this regard. However, recent advances in genomics offer the potential to revolutionize both the speed and certainty of therapeutic target identification. Progress in characterizing the genes in the human genome has been very 25 rapid, and it is now estimated that the entire complement of genes in the human genome may be sequenced before the end of this century. However, this mass of information is coming to the scientific world without a road map. Converting pure gene sequence information into a functional understanding of their role in human disease is proving to be a much more difficult problem. Even after a group of genes is associated with a particular disease, the process of validating which genes are appropriate for use as" therapeutic targets is often slow and costly. Most companies with genomics activities 5 now have access to myriad of partial or full sequences, but do not possess adequate technologies to determine which of those sequences is an appropriate therapeutic target. As a result, only a few genes have been unequivocally identified as the causative agent for a specific disease. The nucleic acid molecules of the present invention can inhibit gene expression i o in a highly specific manner by binding to and causing the cleavage of the mRNA corresponding to the gene of interest, and thereby prevent production of the gene product (Christoffersen, Nature Biotech, 1997, 2, 483-484). Appropriate delivery vehicles can be combined with these nucleic acid molecules (including polymers, cationic lipids, liposomes and the like) and delivered to appropriate cell culture or in i 5 vivo animal disease models as described above. By monitoring inhibition of gene expression and correlation with phenotypic results, the relative importance of the particular gene sequence to disease pathology can be established. The process may be both fast and highly selective, and allow for the process to be used at any point in the development of the organism. The novel chemical composition of these nucleic acid 20 molecules may allow for added stability and therefore increased efficacy. Examples The following are non-limiting examples demonstrating the utility of the nucleic acid molecules of the instant invention. Those in the art will recognize that certain experimental conditions such as temperatures, reaction times, media conditions, 25 transfection reagents, cell types and RNA assays are not meant to be limiting and can be readily modified without significantly altering the protocols. Example 1 : Identification of Potential Binding Sites for the HPH Molecule in the Target Sequence The sequences of target RNAs were screened for accessible sites using a computer-folding algorithm. Regions of the mRNA that did not form secondary 5 folding structures were identified. A more elaborate protocol for identifying appropriate targets may be found in Stinchcomb et al., US Pat. No. 5,646,042 which is incoφorated by reference in its entirety herein. Example 2: Down-Regulation of c-raf Expression HPH oligonucleotides targeting exon 11 of the human c-raf gene, with 4-6 i o complementary nudeotides at the 5' and the 3' end were synthesized using standard protocols (Wincott et al, supra). These 5' and 3' sequences were not complementary to the c-raf target. Of the 23 nudeotides complementary to the target sequence, 11 nudeotides in the DNA core and RNA arms were exchanged to generate a control molecule which lacks the capability to down-regulate c-raf mRNA in a sequence- 1 5 specific manner. The sequences for nucleic acid molecules used are displayed in table III. Tissue Culture and Nucleic Acid delivery Protocol: Prostate cancer cells (PC-3) were grown in a growth media consisting of Kaighn's F-12K media, 10% FBS, 1% glutamine, 20 mM HEPES, and 1% pen/strep to sub-confluent densities. A 4X θ concentration (10 μg/mL) of GSV (Glen Research) was prepared from a 2 mg/mL stock solution as well as a lOμM solution of the nucleic acid molecule of the present invention and its antisense control. Complexes of antisense and GSV were formed in a 96-well plate by channel pipetting in antisense and GSV to form complex solutions which are twice the final concentrations. 25 Inhibition of c-raf mRNA Using Nucleic acid Molecules of Varying Lengths: Using the cell culture and oligonucleotide delivery method described above, PC-3 cells were treated for 1, 3 or 5 days with lipid-complexed haiφin oligonucleotides. The oligonucleotides used were either 31 (Seq. I.D. No. 12022), 33 (Seq. I.D. No. 12021), or 35 nudeotides (Seq. I.D. No. 12020) in length. Mismatch controls were used to check for non-specific effects and are given above as Seq. I.D. Nos. 12023, 12024, and- 12025 for 35, 33, and 31mers, respectively. An untreated control was also tested to 5 determine basal levels of c-raf. PC-3 cells were then harvested with 150 μL of RLT lysis buffer (Qiagen). RNA was purified using Qiagen' s instructions and RNA was quantified using TaqMan™ (Perkin Elemer) reagents and the 7700 Prism (Perkin Elmer) using the manufacturer's protocol. The ratio of c-raf mRNA over β-actin mRNA was determined by real-time PCR after reverse transcription. Results are shown in Fig. i o 3-5. The results show that all three molecules demonstrate high levels of reduction of c-raf RNA compared to the mismatch controls regardless of oligonucleotide length. Inhibition levels ranged from 80-93% in PC-3 cells. After each designated time period, PC-3 cells were harvested with 150 μL of RLT lysis buffer (Qiagen). RNA was 15 purified using Qiagen' s instructions and RNA was quantified using TaqMan™ reagents and the 7700 Prism (Perkin Elmer) using the manufacturer's protocol. The ratio of c-raf mRNA over β-actin mRNA was determined by real-time PCR after reverse transcription. o Example 3 : Comparison of c-raf inhibition between the Haiφin Hybridizer Molecule and a Linear Antisense Molecule. To test whether the nucleic acid molecules of the present invention could inhibit c-raf mRNA as well as linear antisense molecules, haiφin and linear antisense molecules were synthesized (Wincott et al., supra). Using the cell culture and 5 oligonucleotide delivery method described in example 2, PC-3 cells were treated for 1,3 or 5 days with lipid-complexed haiφin oligonucleotides or a lipid complexed linear antisense molecule. The haiφin molecule (Seq. I.D. No. 5) was 31 nudeotides in length and the results of c-raf inhibition were compared to a mismatch control (Seq. I.D. No. 6). The potency of the antisense molecule was also compared to its mismatch control. After each designated time period, PC-3 cells were harvested with 150 μL of RLT lysis buffer (Qiagen). RNA was purified using Qiagen's instructions and RNA ~ was quantified using TaqMan™ reagents and the 7700 Prism (Perkin Elmer) using the 5 manufacturer's protocol. The ratio of c-raf mRNA over β-actin mRNA was determined by real-time PCR after reverse transcription. The data is given in figures 7 and 8. The HPH molecules significantly reduce the c-raf RNA level while the mismatch molecules did not cause any significant reduction (figure 6, 7). Similarly, the linear antisense molecule reduced r-raf RNA levels significantly. These experiments demonstrate that i o the magnitude of c-raf inhibition caused by a haiφin oligonucleotide is comparable with a linear molecule lacking the 5' and 3' haiφin complementary ends Example 4: Mutation Analysis of the Haiφin Hybridizer Molecule The nucleic acid molecules of the present invention were designed to bind to c- 1 5 raf message (table II) with 0, 1 , 2, or 4 mismatches within the internal DNA sequence. The molecules were designed such that the 5' sequence is complementary to both the 3' sequence as well as the target molecule. These molecules were delivered to PC-3 cells using the cell culture and oligonucleotide delivery protocol, described in example 2. The lipid/nucleic acid molecule complexes were added to the cells and allowed to 2θ associate for 24 hours. PC-3 cells were then harvested with 150 μL of RLT lysis buffer (Qiagen). RNA was purified using Qiagen's instructions and RNA was quantified using TaqMan™ reagents and the 7700 Prism (Perkin Elmer) using the manufacturer's protocol. The ratio of c-raf mRNA over β-actin mRNA was determined by real-time PCR after reverse transcription. The results are shown in figure 9. Just a single 25 mutation within the HPH nucleic acid molecule is sufficient to destroy the inhibitory effects of the HPH molecule. This shows that the HPH molecules of the present invention are highly sequence-specific reagents. Example 5: Inhibition of IMDPH II RNA Expression With Haiφin Hybridizing Molecules of Varying Lengths. Prostate cancer cells (PC3) were grown as described above. Nucleic acids were complexed and applied to cells as described, with the exception that a cationic lipid was 5 used. The final oligonucleotide concentration was 100 nM. RNA levels were measured by TaqMan™ analysis as described above. Using the cell culture and oligonucleotide delivery method described above, PC3 cells were treated for 24 hours with lipid-complexed oligonucleotides. The oligonucleotides targeted to IMPDH II had, in one case, a 23mer target-hybridizing i o region plus a 6 base haiφin hybridizing region at the 3' end that annealed to the 5' end (Seq. ID No.l l, and 2 base mismatch control Seq. ID No. 12). Alternatively, the oligonucleotide had a 19mer target-hybridizing region plus a 4 base haiφin-hybridizing region at the 3' end that annealed to the 5' end (Seq. ID No. 13, and 2 base mismatch control Seq. ID No. 14). As shown in Fig. 12, the haiφin hybridizer molecule 1 5 demonstrated 45-70% inhibition of the target RNA level relative to untreated cells. In both cases a 2 base mismatch was sufficient to prevent target down-regulation, demonstrating the high specificity of these reagents. Example 6: Alternative Haiφin Annealing Domains Confer Comparable Efficacy in Cell Culture. θ Using the cell culture and oligonucleotide delivery method described above, PC3 cells were treated for 24 hours with lipid-complexed oligonucleotides. The oligonucleotides targeted c-Raf exon 11, and consisted of DNA core regions (an example of RNase H-activating Region) at or near the 5' end of the oligonucleotide, and a 3' haiφin hybridizing regions that could anneal to different regions of the target- 5 complementary region, including the DNA core and/or the RNA arms. As shown in Fig. 11, a 21mer target-hybridizing region with a 6 base haiφin that anneals to the 5' end of the oligo overlapping part of the DNA core (Seq. ID No. 15) shows greater than 80% inhibition of target RNA expression. Scrambling the 3' end to prevent formation of an intramolecular haiφin (Seq. ID No. 16) neither enhances nor interferes with the θ cell efficacy in this assay, indicating that the oligonucleotide may be able to basepair to the target RNA equivalently with or without the haiφin structure. An 18mer target- hybridizing (complementary) region with varying 6 nucleotide self-complementary structures (Seq. ID Nos. 17, 18, 19, 20) shows 35-65% inhibition of target RNA expression, indicating that a variety of structures can result in efficacious molecules- The difference in magnitude between the 21 mer and 18mer structures probably reflects 5 the lower target binding affinity of the 18mer. The differences in magnitude of inhibition between Seq. ID Nos. 17, 18, 19, 20 may reflect subtle sequence dependence variations in the optimal structure. Using the cell culture and oligonucleotide delivery method described above, PC3 cells were treated for 24 hours with lipid-complexed oligonucleotides. The i o oligonucleotides targeted IMPDH II, and consisted of DNA core regions in the center of the oligonucleotide, and a 3' haiφin hybridizing regions that could anneal to the DNA core. As shown in Fig. 13, a linear antisense oligonucleotide with a 23mer target- hybridizing region (Seq. ID No. 22) gave 70% inhibition, while random sequence and scrambled sequence negative controls (Seq. ID No. 21, 23) gave virtually no inhibition. 15 Haiφin oligos (Seq. ID No. 24, 25) with either a 4-or a 6-base haiφin that anneals to the DNA core showed 60-70% inhibition of target RNA expression. In another example, a linear oligo targeting a different site in the target RNA (Seq. ID No. 26) gave 80%) inhibition, and haiφin oligos (Seq. ID Nos. 27, 28) gave 70-80%) inhibition of target RNA expression. θ Those skilled in the art will recognize that the instant invention is not limited to the HPH molecules used in the foregoing examples. The instant invention broadly features HPH oligonucleotides of varying structures, including those hybridizing to an internal RNase H-activating regions, hybridizing to both the RNase H-activating region and the Non-RNase H-activating region, and those hybridizing to a RNase H-activating 25 region at either the 5' or 3' end (for example see Figures 1-3 and 10). The haiφin structure could provide protection against exonucleolytic and/or endonucleolytic degradation, thus increasing stability both in vivo and in vitro. The haiφin creates a duplex region that juxtaposes various chemical end-modifications that may confer altered in vivo pharmacokinetics or tissue distribution. Thus these θ molecules may have advantages compared to traditional linear antisense molecules for use as therapeutics or as tools for in vivo target validation. Diagnostic uses Nucleic acid molecules of this invention may be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of 5 specific RNAs in a cell. The close relationship between antisense activity and the structure of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional structure of the target RNA. By using multiple nucleic acid molecules described in this invention, one may map nucleotide changes which are important to RNA structure and function in vitro, as i o well as in cells and tissues. Inhibition of target RNAs with nucleic acid molecules may be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets may be defined as important mediators of the disease. These experiments will lead to better treatment during disease progression by affording the possibility of combinational 15 therapies (e.g., multiple nucleic acid molecules targeted to different genes, nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of nucleic acid molecules and/or other chemical or biological molecules). Other in vitro uses of nucleic acid molecules of this invention are well known in the art, and include detection of the presence of RNAs related to various 2θ conditions. All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incoφorated by reference to the same extent as if each reference had been incoφorated by reference in its entirety individually. 25 One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are 5 defined by the scope of the claims. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims. i o The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed i 5 are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred 2o embodiments, optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims. In addition, where features or aspects of the invention are described in terms of 25 Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group. Other embodiments are within the following claims. Table I: 0.2 μmol RNA Synthesis Cycle Reagents Equivalents Amounts CD Wait time (sec) Phosphoramidites 15 31 465 SET 38.7 31 465 Acetic anhydride 655 124 5 N-methyl- 1245 124 5 imidazole TCA 700 732 10 Iodine 20.6 244 15 Wait time does not include contact time during delivery. Table II. Linear Antisense Nucleic Acid Molecules Targeting C-raf With Sequence Mismatches Legend lower case - 2'-O-methyl ribonucleotides uppercase - deoxy-ribonucleotides - phosphorothiote linkage Table III. HPH Molecules Targeting c-raf RNA with Mismatches Legend: lower case 2'-O-methyl ribonucleotides uppercase deoxy-ribonucleotides s phosphorothiote linkage underlined mismatches. Table IV: HPH Molecules targeting IMPDH and c-Raf RNA -0 Legend Lowercase - 2'-0-metlιyl Uppercase - deoxyriboπucleotides ' s - phosphorothioate linkage B- 3'-3' or 5'-5' inverted abasic deoxynucleotide Underline- annealing region Bold- target mismatch SCR- Self-complementary region

Claims: CLAIMS 1. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a hairpin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence expression, wherein said hairpin hybridizer nucleic acid molecule consists of the formula I: B B' wherein, each P, Y, N, and M represents independently a nucleotide which may be the same or different; • indicates hydrogen bond formation between two adjacent nudeotides; N' is a nucleotide complementary to N; o is an integer greater than or equal to 3; w is an integer greater than or equal to 4; k and t are independently zero or an integer greater than or equal to 3; wherein when t or k is independently 3 or greater, at least one said P is not a 2'-H containing nucleotide; each said (P) t and (P) k includes intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, phosphorodithioate, 5 'thiophosphate, and methylphosphonate; (M) w is an oligonucleotide including one or more intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, 5 'thiophosphate, methylphosphonate, and phosphorodithioate linkage; wherein at least one or more of each said (P)t, (P)k, and (M) w is an oligonucleotide is of sufficient length to stably interact with the target sequence; r and f are independently an integer greater than or equal to zero; each B and B' independently represent, a cap structure which may independently be present or absent; and represents a chemical linkage. 2. The method of Claim 1, wherein k in said hairpin hybridizer nucleic acid molecule is less than 100. 3. The method of Claim 2, wherein, k in said hairpin hybridizer nucleic acid molecule is selected from the group consisting of 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, and 20. 4. The method of claim 1, wherein, t in said hairpin hybridizer nucleic acid molecule is less than 100. 5. The method of claim 4, wherein, t in said haiφin hybridizer nucleic acid molecule is selected from the group consisting of 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, and 20. 6. The method of claim 1 , wherein, k and t in said haiφin hybridizer nucleic acid molecule are of the same length. 7. The method of claim 1 , wherein, k and t in said haiφin hybridizer nucleic acid molecule are of different lengths. 8. The method of claim 1, wherein w in said haiφin hybridizer nucleic acid molecule is less than 100. 9. The method of claim 8, wherein w in said haiφin hybridizer nucleic acid molecule is selected from the group consisting of 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, and 20. 10. The method of claim 1 , wherein the t, k, and w in said haiφin hybridizer nucleic acid molecule are of same length. 11. The method of nucleic acid molecule of claim 1, wherein t, k, and w in said haiφin hybridizer nucleic acid molecule are of different length. 12. The method of claim 1, wherein the target sequence is selected from the group consisting of RNA, DNA and RNA/DNA mixed polymers. 13. The method of claim 1, wherein r and f in said haiφin hybridizer nucleic acid molecule are independently selected from the group consisting of 1, 2, 3, 4, 5, 10, and 15. 14. The method of claim 1, wherein the chemical linkage in said haiφin hybridizer nucleic acid molecule is selected from the group consisting of phosphate ester linkage, amide linkage, phosphorothioate, 5'-thiopohisphate, methylphosphonate, and phosphorodithioate. 15. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of the formula II: (M)w / \ (P)k (P)t \ / (N • N')o / \ (P)M (P)« \ / (M)w wherein, each P, N, and M represents independently a nucleotide which may be same or different; • indicates hydrogen bond formation between two adjacent nudeotides, N' is a nucleotide complementary to N; o is an integer greater than or equal to 3; w is an integer greater than or equal to 4; k, t, k, and tj are independently zero or an integer greater than or equal to 3; wherein when t, k, tl, or kl are independently 3 or greater at least one said P is not a 2'-H containing nucleotide; each said (P)„ (P) k , (P) tl , and (P) kl independently include intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, phosphorodithioate, 5 'thiophosphate, and methylphosphonate; (M) w is an oligonucleotide sequence including one or more intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, 5 'thiophosphate, methylphosphonate, and phosphorodithioate linkers; wherein at least one or more of each said (P)„ (P) k , (P)„, (P) k ,and (M) w is an oligonucleotide of sufficient length to stably interact independently with the target sequence; and represents a chemical linkage. 16. The method of claim 15, wherein each k, t, kl, tl and w in said haiφin hybridizer molecule is less than 100. 17. The method of claim 16, wherein each k, t, kl, tl and w in said haiφin hybridizer nucleic acid molecule is independently selected from the group consisting of 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, and 20. 18. The method of claim 15, wherein k and t in said haiφin hybridizer nucleic acid molecule are of same length. 19. The method of claim 15, wherein k and t in said haiφin hybridizer nucleic acid molecule are of different length. 20. The method of claim 15, wherein t, k, and w in said haiφin hybridizer nucleic acid molecule are of the same length. 21. The method of claim 15, wherein t, k, and w in said haiφin hybridizer nucleic acid molecule are of different length. 22. The method of claim 15, wherein tl , kl , and w in said haiφin hybridizer nucleic acid molecule are of the same length. 23. The method of claim 15, wherein tl , kl , and w in said haiφin hybridizer nucleic acid molecule are of different length. _ 24. The method of claim 15, wherein the target sequence is selected from the group consisting of an RNA, DNA and RNA/DNA mixed polymer. 25. The method of claim 15, wherein said chemical linkage in said haiφin hybridizer nucleic acid molecule is selected from the group consisting of phosphate ester linkage, amide linkage, phosphorothioate, 5 '-thiophosphate, methylphosphonate, and phosphorodithioate. 26. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula III: (M)w \ / (N • N') 0 I B B' wherein, each P, N, and M represents independently a nucleotide which may be same or different; • indicates hydrogen bond formation between two adjacent nudeotides, N' is a nucleotide complementary to N; o is an integer greater than or equal to 3; w is an integer greater than or equal to 4; k and t independently are zero or an integer greater than or equal to 3; wherein when t and k are independently 3 or greater at least one said P is not a 2'-H containing nucleotide; each said (P)t and (P)k includes intemucleotide linkages selected , from the group consisting of phosphodiester, phosphorothioate, phosphorodithioate, 5 'thiophosphate, and methylphosphonate; (M)w is an oligonucleotide sequence including on or more intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, 5'thiophosphate, methylphosphonate and phosphorodithioate; D and E are oligonucleotides independently of length greater than or equal to 4; wherein at least one or more of each said (P) t , (P) k , (M) w , D and E are independently an oligonucleotide of sufficient length to stably interact independently with a target nucleic acid sequence; B and B' independently represent a cap structure which may be present or absent; and represents a chemical linkage. 27. The method of claim 26, wherein each k, t, and w in said haiφin hybridizer nucleic acid molecule is independently less than 100. 28. The method of claim 27, wherein each k, t, and w in said haiφin hybridizer nucleic acid molecule is independently selected from the group consisting of 4, 5, 6, 7, 8, 9, 10,11, 12, 15, and 20. 29. The method of claim 26, wherein k and t in said haiφin hybridizer nucleic acid molecule are of the same length. 30. The method of claim 26, wherein k and t in said haiφin hybridizer nucleic acid molecule are of different length. 31. The method of claim 26, wherein each t, k, and w in said haiφin hybridizer nucleic acid molecule are of the same length. 32. The method of claim 26, wherein each t, k, and w in said haiφin hybridizer nucleic acid molecule are of the same length. 33. The method of claim 26, wherein the target nucleic acid sequence is selected from the group consisting of RNA, DNA and RNA/DNA mixed polymer. 34. The method of claim 26, wherein each D and E oligonucleotides is independently less than 100 nudeotides in length. 35. The method of claim 26, wherein the length of each D and E oligonucleotides is independently selected from the group consisting of 6, 7, 8, 9, 10, 11, 12, 15, 20, and 30 nudeotides. 36. The method of claim 26, wherein D and E oligonucleotides in said haiφin hybridizer nucleic acid molecule are of the same length. 37. The method of claim 26, wherein said oligonucleotides, said D and said E oligonucleotides in said haiφin hybridizer nucleic acid molecule are of different length. 38. The method of claim 26, wherein said chemical linkage is selected from the group consisting of phosphate ester linkage, amide linkage, phosphorothioate, and phosphorodithioate. 39. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula V: wherein, each P, N, F, V, Z, and M represents independently a nucleotide which may be same or different; • indicates hydrogen bond formation between two_ adjacent nudeotides, N' is a nucleotide complementary to N; F' is a nucleotide complementary to F; o is an integer greater than or equal to 3; w is an integer greater than or equal to 4; d is an integer greater than or equal to 3; h is an integer greater than or equal to 2; c is an integer greater than or equal to 0; k and t are independently, zero or an integer greater than or equal to 3; wherein when t and k are independently 3 or greater, at least one said P is not a 2'-H containing nucleotide; each (P), ,(P) k , (V) d and (Z) c includes intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, phosphorodithioate, 5 'thiophosphate, and methylphosphonate; (M)w is an oligonucleotide including one or more intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, 5 'thiophosphate, methylphosphonate and phosphorodithioate linkage; wherein at least one or more of each said (P)t, (P)k, and (M)w is an oligonucleotide of sufficient length to stably interact independently with a target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 40. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula VI: wherein, each P, N, F, Z and M represents independently a nucleotide which may be same or different; • indicates hydrogen bond formation between two_ adjacent nudeotides, N' is a nucleotide complementary to N; F' is a nucleotide complementary to F; o is an integer greater than or equal to 3; k and t are independently, zero or an integer greater than or equal to 3; kl and tl are independently zero or an integer greater than or equal to 3; w is an integer greater than or equal to 4; h is an integer greater than or equal to 2; c is an integer greater than or equal to 0; wherein when t, k, tl, or kl is independently 3 or greater at least one said P is not a 2'-H containing nucleotide; each (P) t ,(P) k , (P) tl ,(P) kl , and (Z) c includes intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, phosphorodithioate, 5 'thiophosphate, and methylphosphonate; (M) w is an oligonucleotide including one or more inter-nucleotide linkerages selected from the group consisting of phosphodiester, phosphorothioate, 5 'thiophosphate, methylphosphonate and phosphorodithioate linkage; wherein at least one or more of each said (P) t , (P) k , (P) t „(P) kl , and (M) w is an oligonucleotide of sufficient length to stably interact independently with a target nucleic acid molecule; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 41. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula VII: wherein, each P, N, F, V, Z, and M represents independently a nucleotide which may be same or different; • indicates hydrogen bond formation between two adjacent nudeotides, N' is a nucleotide complementary to N; F' is a nucleotide complementary to F; o is an integer greater than or equal to 3; w is an integer greater than or equal to 4; d is an integer greater than or equal to 3; h is an integer greater than or equal to 2; c is an integer greater than or equal to 0; k and t are independently, zero or an integer greater than or equal to 3; wherein when t and k are independently 3 or greater, at least one said P is not a 2'-H containing nucleotide; each (P) t ,(P) k , (V) d and (Z) c includes intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, phosphorodithioate, 5 'thiophosphate, and methylphosphonate; (M)w is an oligonucleotide including one or more intemucleotide linkages selected from the group consisting of phosphodiester, phosphorothioate, 5 'thiophosphate, methylphosphonate and phosphorodithioate linkage; wherein at least one or more of each said (P)„ (P) k , and (M) w is an oligonucleotide of sufficient length to stably interact independently with a target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 42. The method of any of claims 39-41, wherein each k, t, and w in said haiφin hybridizer nucleic acid molecule is independently less than 100. 43. The method of claims 42, wherein each k, t, and w in said haiφin hybridizer nucleic acid molecule is independently selected from the group consisting of 4 ^ _ 5. 6. 7. 8. 9. 10.11. 12. 15, and 20. 44. The method of any of claims 39 or 41 wherein d in said haiφin hybridizer nucleic acid molecule is independently selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, and 18. 45. The method of any of claims 39-41 , wherein h in said haiφin hybridizer nucleic acid molecule is independently selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, and 9. 46. The method of any of claims 39-41 , wherein c in said haiφin hybridizer nucleic acid molecule is independently selected from the group consisting of 1, 2, 3, 4, 5. 6. 7. 8. 9. 10. 11. 12. 16, and 18. 47. The method of any of claims 39-41 , wherein o in said haiφin hybridizer nucleic acid molecule is selected from the group consisting to 4, 5, 6, 7, 8 and 9. 48. The method of any of claims 39-41, wherein k and t in said haiφin hybridizer nucleic acid molecule are of the same length. 49. The method of any of claims 39-41, wherein k and t in said haiφin hybridizer nucleic acid molecule are of different length. 50. The method of any of claims 39-41, wherein each t, k, and w in said haiφin hybridizer nucleic acid molecule are of different length. 51. The method of any of claims 39-41, wherein each t, k, and w in said haiφin hybridizer nucleic acid molecule are of the same length. 52. The method of any of claims 39-41, wherein the target sequence is selected from the group consisting of RNA, DNA and RNA/DNA mixed polymer. 53. The method of any of claims 39-41, wherein said chemical linkage is selected from the group consisting of phosphate ester linkage, amide linkage, phosphorothioate, 5 '-thiophosphate, methylphosphonate, and phosphorodithioate. 54. The method of claim 40, wherein each kl and tl in said haiφin hybridizer nucleic acid molecule is independently less than 100. 55. The method of claim 40,wherein each kland tl in said haiφin hybridizer nucleic acid molecule is independently selected from the group consisting of 4, 5, 6, 7, 8, 9, 10,11, 12, 15, and 20. 56. The method of claim 40,wherein each tl, kl, and w in said haiφin hybridizer nucleic acid molecule are of different length. 57. The method of claims 40, wherein each tl, kl, and w in said haiφin hybridizer nucleic acid molecule are of the same length. 58. The method of any of claims 39-41, wherein said F portion of the (F»F') h in the HPH nucleic acid molecule is complementary to a portion of said target sequence. 59. The method of any of claims 39-41, wherein said F' portion of the (F » F') h in the HPH nucleic acid molecule is complementary to said target sequence. 60. The method of any of claims 39-41, wherein said F and said F' portion of the (F » F') h in the HPH nucleic acid molecule is independently complementary to said target sequence. 61. The method of any of claims 1, 15, 26, or 39-41, wherein said N portion of the (N » N')o in the HPH nucleic acid molecule is complementary to a portion of said target sequence. 62. The method of any of claims 1, 15, 26, or 39-41, wherein said N' portion of the (N » N')o in the HPH nucleic acid molecule is complementary to said target sequence. 63. The method of any of claims 1, 15, 26, or 39-41, wherein said N and said N' portion of the (N»N')o in the HPH nucleic acid molecule are independently complementary to said target sequence. 64. The method of any of claims 39-41 wherein, said (Z) c in the HPH nucleic acid molecule is complementary to a target sequence. 65. The method of any of claims 1, 15, 26, or 39-41, wherein each said (P) k , (P)„ (N » N') 0 , and (M) w , in the HPH nucleic acid molecule comprises independently a nucleotide modification selected from the group consisting of: 2'-O-methyl, 2'- O-allyl, 2'-O-methylthiomethyl, L-nucleotides; 2'-C-allyl; 1-5-Anhydrohexytol; 2,6-diaminopurine; 2'-fluoro; 2'-deoxy-2'-amino; 2'-(N-alanyl) amino; 2'-(N- phenylalanyl)amino; 2'-deoxy-2'-(N-b-alanyl) amino; 2'-deoxy-2'-(lysyl) amino; 2'-O-amino; 2'-Deoxy-2'-(N-histidyl) amino; 6-methyl uridine; 5- methyl cytidine; 2'-(N-b-carboxamidine-b-alanyl) amino-2'-deoxy-nucleotide; and xylofuranosyl. 66. The method of claim 1, wherein each said (Y) r and (Y) f in the HPH nucleic acid molecule comprises independently a nucleotide modification selected from the group consisting of: 2'-O-methyl, 2'-O-allyl, 2'-O-methylthiomethyl, L- nucleotides; 2'-C-allyl; 1-5-Anhydrohexytol; 2,6-diaminopurine; 2'-fluoro; 2'- deoxy-2' -amino; 2'-(N-alanyl) amino; 2'-(N-phenylalanyl)amino; 2'-deoxy-2'- (N-b-alanyl) amino; 2'-deoxy-2'-(lysyl) amino; 2'-O-amino; 2'-Deoxy-2'-(N- histidyl) amino; 6-methyl uridine; 5-methyl cytidine; 2'-(N-b-carboxamidine-b- alanyl) amino-2'-deoxy-nucleotide; and xylofuranosyl. 67. The method of claim 15 or 40 wherein each said (P) kl , and (P) tl , in the HPH nucleic acid molecule comprises independently a nucleotide modification selected from the group consisting of: 2'-O-methyl, 2'-O-allyl, 2'-O- methylthiomethyl, L-nucleotides; 2'-C-allyl; 1-5-Anhydrohexytol; 2,6- diaminopurine; 2'-fluoro; 2'-deoxy-2'-amino; 2'-(N-alanyl) amino; 2'-(N- phenylalanyl)amino; 2'-deoxy-2'-(N-b-alanyl) amino; 2'-deoxy-2'-(lysyl) amino; 2'-O-amino; 2'-Deoxy-2'-(N-histidyl) amino; 6-methyl uridine; 5- methyl cytidine; 2'-(N-b-carboxamidine-b-alanyl) amino-2'-deoxy-nucleotide; and xylofuranosyl. 68. The method of claim 26, wherein each said D and E in the HPH nucleic acid molecule comprises independently a nucleotide modification selected from the_ group consisting of: 2'-O-methyl, 2'-O-allyl, 2'-O-methylthiomethyl, L- nucleotides; 2'-C-allyl; 1-5-Anhydrohexytol; 2,6-diaminopurine; 2'-fluoro; 2'- deoxy-2' -amino; 2'-(N-alanyl) amino; 2'-(N-phenylalanyl)amino; 2'-deoxy-2'- (N-b-alanyl) amino; 2'-deoxy-2'-(lysyl) amino; 2'-O-amino; 2' -Deoxy-2 '-(N- histidyl) amino; 6-methyl uridine; 5-methyl cytidine; 2'-(N-b-carboxamidine-b- alanyl) amino-2'-deoxy-nucleotide; and xylofuranosyl. 69. The method of any of claims 39-41, wherein each said (Z) c , and (F»F') h , in the HPH nucleic acid molecule comprises independently a nucleotide modification selected from the group consisting of: 2'-O-methyl, 2'-O-allyl, 2'-O- methylthiomethyl, L-nucleotides; 2'-C-allyl; 1-5-Anhydrohexytol; 2,6- diaminopurine; 2'-fluoro; 2'-deoxy-2'-amino; 2'-(N-alanyl) amino; 2'-(N- phenylalanyl) amino; 2' -deoxy-2 '-(N-b-alanyl) amino; 2' -deoxy-2 '-(lysyl) amino; 2'-O-amino; 2'-Deoxy-2'-(N-histidyl) amino; 6-methyl uridine; 5- methyl cytidine; 2'-(N-b-carboxamidine-b-alanyl) amino-2'-deoxy-nucleotide; and xylofuranosyl. 70. The method of any of claims 39 or 41 wherein each said (V) d , in the HPH nucleic acid molecule comprises independently a nucleotide modification selected from the group consisting of: 2'-O-methyl, 2'-O-allyl, 2'-O- methylthiomethyl, L-nucleotides; 2'-C-allyl; 1-5-Anhydrohexytol; 2,6- diaminopurine; 2'-fluoro; 2 '-deoxy-2 '-amino; 2'-(N-alanyl) amino; 2'-(N- phenylalanyl)amino; 2 '-deoxy-2 '-(N-b-alanyl) amino; 2'-deoxy-2'-(lysyl) amino; 2'-O-amino; 2' -Deoxy-2 '-(N-histidyl) amino; 6-methyl uridine; 5- methyl cytidine; 2'-(N-b-carboxamidine-b-alanyl) amino-2'-deoxy-nucleotide; and xylofuranosyl. 71. The method of any of claims 1, 26, or 39-41, wherein said B' when present, selected from the group consisting of: inverted abasic residue; 4',5'-methylene nucleotide; l-(beta-D-erythrofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha- nucleotides; modified base nucleotide; phosphorodithioate linkage; threo- pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; acyclic 3,4- dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide, 3'-3'-_ inverted nucleotide moiety; 3'-3'-inverted abasic moiety; 3'-2'-inverted nucleotide moiety; 3'-2'-inverted abasic moiety; 1 ,4-butanediol phosphate; 3'- phosphoramidate; hexylphosphate; aminohexyl phosphate; 3'-phosphate; 3'- phosphorothioate; phosphorodithioate; and methylphosphonate moiety. 72. The method of any of claims 1 , 26, or 39-41 , wherein said nucleic acid molecule comprises a 3'-3' linked inverted abasic moiety at said 3' end. 73. The method of any of claims 1, 26, or 39-41, wherein said B when present, is selected from the group consisting of: 4',5'-methylene nucleotide; l-(beta-D- erythrofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; 5'- amino-alkyl phosphate; l,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha- nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5- dihydroxypentyl nucleotide, 5'-5'-inverted nucleotide moiety; 5'-5'-inverted abasic moiety; 5'-phosphoramidate; 5'-phosphorothioate; 1,4-butanediol phosphate; 5'-amino; bridging and/or non-bridging 5'-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5'-mercapto moieties. 74. The method of any of claims 1, 15, 26, or 39-41 wherein said cell is a mammalian cell. 75. The method of any of claims 1, 15, 26, or 39-41 wherein said cell is a plant cell. 76. The method of any of claims 1, 15, 26, or 39-41 wherein said cell is a bacterial cell 77. The method of any of claims 1, 15, 26, or 39-41 wherein said cell is a microbial cell. 78. The method of any of claims 1, 15, 26, or 39-41 wherein said cell is a fungal cell. 79. The mammalian cell of claim 74, wherein said mammalian cell is a human cell. 80. The method of any of claims 1, 15, 26, or 39-41, wherein said HPH nucleic acid molecule is chemically synthesized. 81. The method of any of claims 1, 15, 26, or 39-41, wherein said HPH is a pharmaceutical composition . 82. The method of any of claims 1, 15, 26, or 39-41, wherein said modulation of function is the modulation of the phenotype of the cell. 83. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula IX: B B' I F / D « 0 I I κ * τ \ / w wherein, each F, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; F and D independently form a RNaseH-activating domain, wherein F and D are of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K and T form greater than or equal to two base pairs with each other that are contiguous or noncontiguous; the K»T and O«D base-paired regions within the HPH nucleic acid molecule may be contiguous or non-contiguous to each other; K, T, O, and W are of length greater than or equal to 3 nudeotides; F, D, K, T, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula X: B B' I F I 0 » D I I κ * τ \ / w wherein, each F, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; F and D independently form RNaseH-activating domain, wherein F and D are of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K and T form greater than or equal to two base pairs with each other that are contiguous or noncontiguous; the K»T and O*D base-paired regions may be contiguous or noncontiguous to each other; K, T, O, and W are of length greater than or equal to 3 nudeotides; F, D, K, T, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 85. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XI: B B' 1 F / o « » D 1 1 κ « T \ / w wherein, each F, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; F and D independently or in combination form RNaseH-activating region; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; the K»T and O»D base-paired regions may be contiguous or non-contiguous to each other; K, T, O and W are of length greater than or equal to 3 nudeotides; F, D, K, T, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XII: B B' D - O < > w wherein, each D, O and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5'- thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; O and W are of length greater than or equal to 3 nudeotides; D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XIII: B B' O - D < > W wherein, each D, O and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5'- thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; O and W are of length greater than or equal to 3 nudeotides; D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XIV: B B' I A I O - D i i \ / w wherein, each A, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K>T and O»D base-paired regions may be contiguous or non-contiguous to each other; A, K, T, O and W are of length greater than or equal to 3 nudeotides; A, D, K, T, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XV: B B' I A / 0 * D I I κ « τ \ / w wherein, each A, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K»T and O*D base-paired regions may be contiguous or non-contiguous to each other; A, K, T, O and W are of length greater than or equal to 3 nudeotides; A, D, K, T, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XVI: B B' I A I D « 0 K - T \ / w wherein, each A, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K T and O«D base-paired regions may be contiguous or non-contiguous to each other; A, K, T, O and W are of length greater than or equal to 3 nudeotides; A, D, K, T, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XVII: B B' I A / O I K T \ / w wherein, each A, D, O, K, W and T represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; K comprises nucleotide sequence that is complementary to the nucleotide sequence of T; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K and T form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; K*T and O*D base-paired regions may be contiguous or non-contiguous to each other; A, K, T, O and W are of length greater than or equal to 3 nudeotides; A, D, K, T, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XVIII: B B' I A I O ' D < > W wherein, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; A, O and W are of length greater than or equal to 3 nudeotides; A, D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 92. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XIX: B B' 1 I A I 1 0 • D \ < / \ rø wherein, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5'-thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; A, O and W are of length greater than or equal to 3 nudeotides; A, D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 93. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XX: B B' I F 0 « D < > W wherein, each F, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; F and D independently form an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; O and W are of length greater than or equal to 3 nudeotides; F, D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 94. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XXI: B B' I F I < > W wherein, each F, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; F and D independently or in combination form an RNaseH-activating domain; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; O and W are of length greater than or equal to 3 nudeotides; F, D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 95. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XXII: B 3 1 A I 1 < > W wherein, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; A, O and W are of length greater than or equal to 3 nudeotides; A, D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 96. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XXIII: B B' I A I D » 0 < > W wherein, each A, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5'-thiophosphate, phosphorodithioate, and methylphosphonate; D independently forms an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; A, O and W are of length greater than or equal to 3 nudeotides; A, D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 97. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XXIV: B B' I F I D » 0 / \ \ / W wherein, each F, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5 '-thiophosphate, phosphorodithioate, and methylphosphonate; F and D independently or in combination form an RNaseH-activating domain; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; O and are of length greater than or equal to 3 nudeotides; F, D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. 98. A method of modulating the function of a target sequence in a cell comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the modulation of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule consists of formula XXV: i l l B B' I 1 F I 1 D • O \ < \ W wherein, each F, D, O, and W represents independently an oligonucleotide whose nucleotide sequence may be same or different, may be of same or different length and include individually or in combination, intemucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, 5'-thiophosphate, phosphorodithioate, and methylphosphonate; F and D independently form an RNaseH-activating domain of length greater than or equal to 4 nudeotides; • indicates hydrogen bond formation between two adjacent nudeotides within the HPH nucleic acid molecule; D comprises nucleotide sequence that is complementary to the nucleotide sequence of O; D and O form greater than or equal to two base pairs with each other that are contiguous or non-contiguous; O and W are of length greater than or equal to 3 nudeotides; F, D, W and O together are of sufficient length to stably interact with the target sequence; each B and B' independently represents a cap structure which may independently be present or absent; and represents a chemical linkage. A method of inhibiting the function of a target sequence in a cell, wherein said target sequence is encoded by c-raf gene, comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the inhibition of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule comprises any of sequence selected from the group consisting of Seq ID Nos 1, 15, 17, 18, 19 and 20. A method of inhibiting the function of a target sequence in a cell, wherein said target sequence is encoded by IMPDH II gene, comprising the step of contacting said cell with a haiφin hybridizer (HPH) nucleic acid molecule under conditions suitable for the inhibition of said target sequence function, wherein said haiφin hybridizer nucleic acid molecule comprises any of sequence selected from the group consisting of Seq ID Nos 11, 13, 24, 25, 27 and 28.

Inventors: HARTMANN THOMAS, JARVIS THALE, THOMPSON JAMES, ZWICK MICHAEL, HARTMANN, THOMAS, JARVIS, THALE, THOMPSON, JAMES, ZWICK, MICHAEL
Applicants: HARTMANN THOMAS, JARVIS THALE, RIBOZYME PHARM INC, THOMPSON JAMES, ZWICK MICHAEL, HARTMANN, THOMAS, JARVIS, THALE, RIBOZYME PHARMACEUTICALS, INC., THOMPSON, JAMES, ZWICK, MICHAEL
Application year: 1999
Main classification: C12N15
IPC codes: A61K31, A61K35, A61K38, A61K48, A61P43, C12N1, C12N5, C12N15, C12Q1