CHIMERIC OLIGOMERS HAVING AN RNA-CLEAVAGE ACTIVITY

Abstract: New chimeric oligomers having an RNA-cleavage activity, as well as their use for cleaving RNA-substrates in vitro and in vivo have been disclosed. The new chimeric oligomers contain an active centre, the building blocks of which are selected from nucleotides or/and nucleotide analogues, as well as flanking regions contributing to the formation of a specific hybridization of the oligomer with an RNA-substrate and containing at least one building block which is different from deoxyribonucleotides and ribonucleotides.

Description: Chimeric oligomers having an RNA-cleavagβ activity Description The present invention concerns chimeric oligomers having an RNA-cleavage activity and the use thereof for the cleavage of RNA substrates in vitro and in vivo. Hammerhead ribozymes are an example of catalytic RNA molecules which are able to recognize and cleave a given specific RNA substrate (Hotchins et al . , Nucleic Acids Res. 14 (1986) , 3627; Keese and Symons in: Viroids and viroid - like pathogens, J.J. Semanchik, Publ . (CRC-Press, Boca Raton, Florida, (1987) , p. 1 - 47) . The catalytic centre of hammerhead ribozymes contains three stems and can be formed by adjacent sequence regions of the RNA or also by regions which are separated from one another by many nucleotides. Fig 1 shows a diagram of such a catalyti- cally active hammerhead structure. The stems have been denoted I, II and III. The nucleotides are numbered according to the standard nomenclature for hammerhead ribozymes (Hertel et al . , Nucleic Acids Res. 20 (1992) , 3252) . The consensus sequence of the catalytic core structure is des¬ cribed by Ruffner and Uhlenbeck (Nucleic Acids Res. 18 (1990) , 6025-6029) . Perriman et al . (Gene 113 (1992) , 157 - 163) have meanwhile shown that this structure can also contain variations e.g. naturally occurring nucleotide insertions such as N 9λ and N , or modifications that can be tolerated such as R ' =G. Thus the positive strand of the satellite RNA of the tobacco ring-spot virus does not contain any of the two nucleotide in¬ sertions while the +RNA strand of the virusoid of the lucerne transient streak virus (vLTSV) contains a N = U insertion which can be mutated to C or G without loss of activity (Shel¬ don and Symons, Nucleic Acids Res. 17 (1989) , 5679-5685) . Fur- thermore in this special case N 7 = A and R15 1 = A. On the other hand the minus strand of the carnation stunt associated viroid (- CarSV) is quite unusual since it contains both nucleotide insertions i.e. N X12 = A and N 9λ = C (Hernandez et al . , Nucleic Acids Res. 20 (1992), 6323-6329) . In this viroid N 7 = A and R " = A. In addition this special hammerhead structure exhi¬ bits a very effective self-catalytic cleavage despite the more open central stem. The possibilities of using hammerhead RNA enzymes range from the isolation of RNA restriction enzymes to the specific inac- tivation of the expression of genes in cells e.g. in animal, human or plant cells and in prokaryotes, yeasts and plasmodia. A particular biomedical interest is based on the fact that many diseases, including many forms of tumours, are related to the expression of specific genes. Inactivating such genes by clea¬ ving the associated mRNA could represent a possible way to con¬ trol and eventually treat such diseases. Moreover there is a great need to develop antiviral or antimicrobial pharmaceutical agents, the RNA enzymes possibly being such an agent, since viral expression can be blocked selectively by cleaving viral or microbial RNA molecules. The most promising variants of pharmaceutical agents for the specific inactivation of the expression of genes are modified oligonucleotides which contain a block of deoxyribonucleotides in the middle region of the molecule (Giles et al . , Nucleic Acids Res. 20 (1992) , 763 - 770) . These deoxyribonucleotides form a DNA-RNA hybrid with RNA the RNA strand of which is clea¬ ved by cellular RNAse H. However, a disadvantage of these oli¬ gonucleotides for in vivo applications is their low specifici¬ ty, since hybrid formation and thus cleavage can also take place at undesired positions on the RNA molecules. In addition the DNA sequences interact undesirably with cellular proteins. Previous attempts to recombinantly express catalytically active RNA molecules of the cell by transfecting the cell with an ap¬ propriate gene have not proven to be very effective since a very high expression was necessary to inactivate specific RNA substrates. In addition the vector systems which are available now cannot generally be applied. Furthermore unmodified RNA enzymes cannot be administered directly due to the sensitivity of RNA to degradation by RNAses and their interactions with proteins . Thus chemically modified active substances have to be admini¬ stered in order to administer hammerhead ribozymes exogenously (cf. e.g. Heidenreich et al . , J. Biol. Chem. 269 (1994) , 2131- 2138; Kiehntopf et al . , EMBO J. 13 (1994) , 4645-4652; Paolella et al., EMBO J. 11 (1992) , 1913-1919 and Usman et al . , Nucleic Acids Symp. Ser. 31 (1994) , 163-164) . DE-OS 42 16 134 describes such chemically modified active sub¬ stances based on synthetic catalytic oligonucleotide structures with a length of 35-40 nucleotides which are suitable for clea¬ ving a nucleic acid target sequence and contain modified ribo- nucleotides that contain an optionally substituted alkyl, alke- nyl or alkynyl group with 1 - 10 carbon atoms at the 2'-0 atom of the ribose. Furthermore oligonucleotides are described which contain the above-mentioned modified nucleotide building blocks and which form a hammerhead structure. These oligonucleotides are able to cleave specific RNA substrates. Examples of oligo¬ nucleotides are described having an active centre which has a length of 14 nucleotides. This active centre contains several ribonucleotides that increase the sensitivity towards enzymes which cleave RNA. A further disadvantage is the length of the active centre which can often lead to unspecific hybridization. WO 95/11304 describes RNA-cleaving nucleic acids with an active centre that is free of ribonucleotide building blocks but in¬ stead contains deoxyribonucleotides . However, the deoxyribonu¬ cleotides used in the active centre result in a very low RNA cleavage activity. Thus it was reported that a 13-mer deoxyri- bozyme of the "GAAA" type based on LTSV was not able to cleave a 41-mer oligoribonucleotide substrate while the corresponding 13-mer ribozyme exhibited an excellent catalytic activity (Jef¬ fries and Symons, Nucleic Acids Res. 17 (1989) , 1371-1377) . In addition the use of a larger number of deoxyribonucleotide building blocks in the hybridization arms or in the active cen¬ tre leads to loss of specificity due to an activation of RNAse H since sequences which are related to the desired target se¬ quence can also be cleaved. Moreover catalytic DNA oligomers are not particularly well suited for in vivo applications due to interactions with proteins. The object of the present invention was therefore to provide chimeric oligomers that cleave RNA in which the disadvantages of the state of the art are at least partially eliminated. In particular it is intended to provide chimeric RNA-cleaving oli¬ gomers which at the same time have a high stability and a high effectivity and specificity as well as being suitable for in vivo applications. This object is achieved by a chimeric oligomer having RNA clea¬ vage activity which has a structure of formula (I) : 5'-X-Z-Y-3' (I) in which X and Y represent oligomeric sequences containing building blocks composed of nucleotides or/and nucleotide ana¬ logues and contribute to the formation of a specific hybridiza¬ tion of the oligomer with an RNA substrate, in which X and Y each contain at least one building block that differs from deoxyribonucleotides and ribonucleotides in which Z represents the active centre of the chimeric oligo¬ mer having a structure of formulae (Ilia) , (Illb) , (IVa) or (IVb) : 5- -G 12 -A 13 A 14 R 15 1 -3' (Ilia) 5 ' -N λl2 G 12 A 13 A 1 R 15 1 - 3 ' ( I Hb ) 5 ' - C 3 U 4 G 5 A 6 N G 8 A 9 - 3 ' ( IVa ) 5 ' - C 3 U"G 5 A 6 N 7 G 8 A 9 N 9λ - 3 ' ( IVb ) in which the building blocks of the structures (Ilia) , (Illb) , (IVa) , (IVb) are selected from nucleotides or/and nucleotide analogues in which the building blocks have a structure of formula (II) : in which B denotes a residue which is a naturally occurring nucleobase or fi functional equivalent thereof, in particular selected from the group comprising adenin-9-yl (A) , cytosin-1- yl (C) , guanin-9-yl (G) , uracil-1-yl (U) , uracil-5-yl ) , hy- poxanthin-9-yl (I) , thymin-1-yl (T) , 5-methylcytosin-l-yl (5MeC) , 2 , 6-diaminopurin-9-yl (aminoA) , purin-9-yl (P) , 7-de- azaadenin-9-yl (c 7A) , 7-deazaguanin-9-yl (c7G) , 5-propynylcyto- sin-l-yl (5-pC) , 5-propynyluracil-l-yl (5-pU) , isoguanin-9-yl , 2-aminopurin-9-yl, 6-methyluracil-1-yl, 4-thiouracil-1-yl, 2- pyrimidone-1-yl and quinazoline-2, 4-dione-1-yl ; V independently denotes an 0, S, NH or CH 2 group W independently denotes an H or OH or a straight-chained or branched alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl or alky- nyloxy with 1 to 10 C atoms which can be optionally substituted by one or several halogen, cyano, amino, carboxy, ester, ether, carboxamide, hydroxyl or/and mercapto groups or is selected from -COOH, -CONH 2 , -CONHR 1 , -CONR 1 R 2 , -NH 2 , -NHR 1 , -NR X R 2 , -NHCOR 1 , -SH, -SR 1 , -F, -ONH 2 , -ONHR 1 , -0NR 1 R 2 , -NHOH, -NHOR 1 , -NR OH and NR 2 OR 1 in which R and R independently denote unsub¬ stituted or substituted alkyl, alkenyl or alkynyl groups as defined above, D and E denote residues which together form a phosphodiester or phosphorothioate diester bond between adjacent nucleosides or analogues or together form an analogue of an internucleosidic bond, in which the structures (Ilia) or (Illb) do not contain a total of more than two deoxyribonucleotides and the structures (IVa) or (IVb) do not contain a total of more than four deoxyribonu¬ cleotides and in which G in each case independently denotes a building block according to formula (II) in which B is guanin-9-yl or a functional equivalent thereof for that particular location in the ham¬ merhead core structure, which is preferably selec¬ ted from I, c 7 G and isoguanin-9-yl; A in each case independently denotes a building block according to formula (II) in which B is adenin-9-yl or a functional equivalent thereof for that particular location in the ham¬ merhead core structure, which is preferably selec¬ ted from aminoA, P, c 7 A and 2-aminopurin-9-yl ; U in each case independently denotes a building block according to formula (II) in which B is uracil-1-yl or a functional equivalent thereof for that particular location in the ham¬ merhead core structure, which is preferably selec¬ ted from ψ , T, 5-pU, 6-methyluracil-l-yl, 4-thio- uracil-1-yl, 2-pyrimidone-l-yl and quinazoline- 2, 4-dione-l-yl; C in each case independently denotes a building block according to formula (II) in which B is cytosin-1-yl or a functional equivalent thereof for that particular location in the ham¬ merhead core structure, which is preferably selec¬ ted from 5MeC, 5-pC and 2-pyrimidone-l-yl; R in each case independently denotes a building block according to formula (II) in which B independently denotes G or A as defined above, N in each case independently denotes a building block according to formula (II) . The monomeric building blocks of sequences X and Y which flank the active centre are nucleotide or/and nucleotide analogues and are selected in such a way that they specifically hybridize with a given RNA substrate and, together with the active centre Z, form a structure, especially a hammerhead structure which specifically cleaves the RNA substrate. The nucleotide building blocks can, on the one hand, be selec¬ ted from ribonucleotides . However, the number of ribonucleoti- des should be as small as possible since the presence of ribo- nucleotide building blocks strongly reduces the in vivo stabi¬ lity of the oligomers. The flanking regions X and Y (and also the active centre Z) should in particular not contain any na¬ tural ribonucleotide building blocks at the positions taken up by pyrimidine nucleotides but rather modified building blocks. The use of a larger number of deoxyribonucleotides for the flanking sequences X and Y is also less preferred since undesi- red interactions with proteins can occur or the formation of an RNAse H-sensitive DNA-RNA hybrid. Thus the flanking sequences each preferably contain at most 1 and particularly preferably no ribonucleotide at all and a consecutive sequence of a maxi¬ mum of 3 deoxyribonucleotides and especially no more than 2 deoxyribonucleotides . The building blocks of the flanking sequences X and Y are pre¬ ferably selected from nucleotides or/and nucleotide analogues e.g. from building blocks having the structure (II) which are also used for the active centre Z. Preferred modified building blocks are those in which W is in each case independently se¬ lected from optionally substituted alkyl, alkoxy, alkenyl, al- kenyloxy, alkynyl or alkynyloxy residues with 1 - 10 C atoms. Particularly preferred substituents are for example methyl, ethyl, propyl, allyl, methoxy, ethoxy, propoxy, allyloxy, hy- droxyethyloxy and ethoxyethyloxy. However, other modified building blocks can also be used such as nucleotide analogues which contain amino groups, substituted amino groups, halogen groups or sulfhydryl groups at the 2' position of pentose . The internucleosidic linkage between two nucleoside building blocks can be achieved by phosphodiester bonds or by modified phospho bonds such as by phosphorothioate groups or other bonds such as for example those described in DE-OS 42 16 134. In addition the flanking regions X and Y can also contain nu¬ cleotide analogues such as peptidic nucleic acids (see for ex¬ ample Nielsen et al . , Science 254 (1991) , 1497-1500 and Dueholm et al . , J. Org. Chem. 59 (1994) , 5767-5773) . In this case the linkage of individual building blocks can for example be achie¬ ved by acid amide bonds. The linkage of flanking regions X and Y which are based on peptidic nucleic acids with an active cen¬ tre Z based on nucleotide building blocks can either be achie¬ ved by suitable linkers (see e.g. Petersen et al . , BioMed. Chem. Lett. 5 (1995) , 1119-1121) or directly (Bergmann et al . , Tetrahedron Lett . 36 (1995) , 6823-6826. The flanking regions X and Y preferably contain independently of each other 3 - 40 and particularly preferably 5 - 10 nucleo¬ tide or nucleotide analogue building blocks. The building blocks of the flanking regions X and Y contain nucleobases or analogues which can hybridize with bases that occur naturally in RNA molecules. The nucleobases are prefer¬ ably selected from naturally occurring bases (adenine, guanine, cytosine, thymine and uracil) as well as analogues thereof e.g. 2 , 6-diaminopurine, hypoxanthine, 5-methylcytosine, pseudoura- cil, 5-propynyluracil, 5-propynylcytosine etc. which enable a specific binding to the target RNA. A firm binding to the RNA substrate is preferred in the regions X and Y so that the following nucleobases are particularly pre¬ ferred as building blocks: 2, 6-diaminopurine instead of adeni- ne; thymine or 5-propynyluracil instead of uracil; 5-methylcy- tosine or 5-propynylcytosine instead of cytosine. In addition 2-amino-2' -O-alkyladenosines are preferred (Lamm et al . , Nu¬ cleic Acids Res. 19 (1991) , 3193-3198) . Furthermore aromatic systems can be linked to positions 4 and 5 of uracil, such as B = phenoxazine by which means dramatic improvements are obtained in the stability of the double-strand (Lin et al . , J. Am. Chem. Soc. 117 (1995) , 3873-3874) . The 3' end of the oligomer according to the invention can ad¬ ditionally be protected against degradation by exonucleases for example by using a modified nucleotide building block that is also modified at the 3' position of the ribose sugar e.g. by an optionally substituted alkyl, alkoxy, alkenyl, alkenyloxy, al¬ kynyl or alkynyloxy group as defined above. An additional pos¬ sibility of further stabilizing oligomers according to the in¬ vention at the 3' end against degradation by exonucleases is a 3 ' -3' -linked dinucleotide structure or/and the presence of two modified phospho bonds such as two phosphorothioate bonds . Moreover the chimeric oligomer structure according to the in¬ vention can be linked to a prosthetic group in order to improve its cellular uptake or/and to enable a specific cellular loca¬ lization. Examples of such prosthetic groups are polyamino acids (e.g. polylysine) , lipids, hormones or peptides . These prosthetic groups are usually linked via the 3' or 5' end of the oligomer either directly or by means of suitable linkers (e.g. linkers based on 6-aminohexanol or 6-mercapto-hexanol etc.) . These linkers are commercially available and techniques suitable for linking prosthetic groups to the oligomer are known to a person skilled in the art. The increase in the rate of hybridization is particularly im¬ portant for the biological activity of the oligomers according to the invention since in this way it is possible to achieve a high activity at low concentrations. This is particularly im¬ portant for short-lived RNA substrates or RNA substrates that occur less often. A substantial acceleration of the hybridiza- tion can for example be achieved by coupling positively charged peptides, which for example contain several lysine residues, to the end of an oligonucleotide (Corey, J. Am. Chem. Soc. 117 (1995) , 9373-9374) . A chimeric oligomer according to the inven¬ tion can be simply modified in this manner using the linkers described above. Alternatively the rate of hybridization can also be increased by incorporation of building blocks which contain sperminyl residues (Schmid and Behr, Tetrahedron Lett . 36 (1995) , 1447 - 1450) . Such modifications of the chimeric oligomers also improve the ability to bind to RNA substrates having secondary structures. The active centre Z of the chimeric oligomer according to the invention contains nucleotide building blocks which are modi¬ fied and optionally a small number of natural nucleotides i.e. ribonucleoti es or/and deoxyribonucleotides. The nucleotide building blocks in the region Z are preferably selected from compounds which can only hybridize weakly with ribonucleotides such as modified nucleotides that contain an optionally substituted alkyl, alkenyl or alkynyl group with preferably 1-5 C atoms at the 2'-C atom of ribose. In addition substituents are also preferred which are selected from option¬ ally substituted alkoxy, alkenyloxy or alkynyloxy groups with 1-5 C atoms. Particularly preferred nucleobases in the region Z are A or P, U, C and G or I . According to a first embodiment of the present invention the active centre Z of the chimeric oligomer contains a structure of formulae (Ilia) or (Illb) . Such an oligomer can cleave an RNA substrate which contains a structure of formula (Va) or (Vb) : 5 ' -U 16 1 H 17 - S - C 3 U 4 G 5 A 6 N 7 G β A 9 R 10 1 - 3 ' (Va ) 5 ' -U 16 1 H 17 - S - C 3 U 4 G 5 A 6 N 7 G e A 9 N 9λ R 10 1 - 3 ' (Vb ) in which N, H, R, S, G, A, U and C represent ribonucleotides and N denotes G, A, U or C; H denotes A, C or U; R denotes A or G and S is an RNA sequence capable of forming a hairpin structure with a length of preferably 6 - 60 and par¬ ticularly preferably of 6 - 20 bases. An oligomer with an active centre (Ilia) or (Illb) can form the hammerhead structure shown in Fig. 2 with an RNA substrate con¬ taining a structure of formulae (Va) or (Vb) in which the nu¬ cleotides are numbered according to the standard nomenclature. The active centre Z (Ilia) or (Illb) preferably contains no more than four and particularly preferably no more than two ribonucleotides and most preferably no more than one ribonu¬ cleotide . Particularly good results were obtained for oligomers in which G12 is a deoxyribonucleotide, a ribonucleotide or a building block in which W is a C j -C 4 alkyl, alkenyl, alkoxy or alkenyloxy group optionally substituted by OH and in particular a (2-hy- droxyethyloxy) group. A 13 , A 1 * c r/and R 15 * are preferably selec¬ ted from building blocks in which W is preferably a C X - C alkyl, alkenyl, alkoxy or alkenyloxy group optionally substituted by OH and particularly preferably a methoxy, (2-hydroxy-ethyloxy) and allyloxy group. In addition it was also possible to synthe¬ size an oligomer which does not contain any ribonucleotide and any deoxyribonucleotide in the active centre Z. This oligomer contains a 2' -O- (2-hydroxyethyl)guanosine at position G 12 and a 2' -O- (2-hydroxyethyl) adenosine at each of the positions A 13 , A 14 and R 1S 1 . According to a second embodiment of the present invention the active centre of the oligomer has a structure of formulae (IVa) or (IVb) and exhibits cleavage activity for an RNA substrate that contains a structure of formula (Via) or (VIb) : 5' -Y 11 - 1 G 12 A 13 A 1 R ls - 1 -S-U"- 1 H 17 -3' (Via) 5 , _ yll . l N λl2 G 12 A 13 A 14 R 15 1 _ g _ T l 6 . Ijjl 1 _ 3 , ( VIb ) in which N, H, Y, R, S, G, A, U and C represent ribonucleotides and N denotes G, A, U or C H denotes A, C or U R denotes A or G Y denotes C or U and S is an RNA sequence capable of forming a hairpin structure with a length of preferably 6 - 60 and particularly preferably of 6 - 20 bases. An oligomer with an active centre (IVa) or (IVb) forms the ham¬ merhead structure shown in Fig. 3 with an RNA substrate contai¬ ning a structure of formulae (Via) or (VIb) in which the nu¬ cleotides are numbered according to the standard nomenclature. The active centre Z preferably contains no pyrimidine ribonu¬ cleotides. Z preferably contains no more than six and particu¬ larly preferably no more than three ribonucleotides. If the active centre Z contains ribonucleotides, one or several building blocks at positions G 5 , A 6 , N 7 (if N 7 is a purine) , G e , A 9 and N 9λ (if N 9λ is present and is a purine) are thus prefer¬ ably ribonucleotides. The building blocks at positions C 3 , U 4 N 7 (if N 7 is a pyrimidine) and N 9λ (if N 9λ is present and is a pyri¬ midine) are preferably nucleotide analogue building blocks in particular such building blocks in which W is an optionally OH- substituted C α -C 4 alkyl, alkenyl, alkoxy or alkenoxy group or an NH 2 group. Building blocks are especially preferred which can only hybridize very weakly with ribonucleotides in the sub¬ strate such as those nucleotide analogues which contain an op¬ tionally substituted alkyl, alkenyl or alkynyl group according to formula (II) , e.g. an allyl group, at the 2' C atom of the ribose. However, 2' -O-nucleotide analogues are on the other hand also preferred. Specific examples of suitable substituents are methoxy, (2-hydroxyethyloxy) , allyl, allyloxy and NH 2 . In addition N 7 and N 9λ , if they are present, are selected in such a way that a minimum of internal structures can form by internal interactions. The preferred nucleobases in the region Z are A 11 N denotes G, A, U or C; H denotes A, C or U; R denotes A or G and S is an RNA sequence capable of forming a hairpin structure with a length of preferably 6 - 60 and par¬ ticularly preferably of 6 - 20 bases. An oligomer with an active centre (Ilia) or (Illb) can form the hammerhead structure shown in Fig. 2 with an RNA substrate con¬ taining a structure of formulae (Va) or (Vb) in which the nu¬ cleotides are numbered according to the standard nomenclature. The active centre Z (Ilia) or (Illb) preferably contains no more than four and particularly preferably no more than two ribonucleotides and most preferably no more than one ribonu¬ cleotide. Particularly good results were obtained for oligomers in which G12 is a deoxyribonucleotide, a ribonucleotide or a building block in which W is a C j -C 4 alkyl, alkenyl, alkoxy or alkenyloxy group optionally substituted by OH and in particular a (2-hy- droxyethyloxy) group. A 13 , A 14 c r/and R 15 ' 1 are preferably selec¬ ted from building blocks in which W is preferably a C 1 - C alkyl, alkenyl, alkoxy or alkenyloxy group optionally substituted by OH and particularly preferably a ethoxy, (2-hydroxy-ethyloxy) and allyloxy group. In addition it was also possible to synthe¬ size an oligomer which does not contain any ribonucleotide and any deoxyribonucleotide in the active centre Z. This oligomer contains a 2' -O- (2-hydroxyethyl)guanosine at position G 12 and a 2' -O- (2-hydroxyethyl) adenosine at each of the positions A 13 , A 14 and R 15 1 . According to a second embodiment of the present invention the active centre of the oligomer has a structure of formulae (IVa) or (IVb) and exhibits cleavage activity for an RNA substrate that contains a structure of formula (Via) or (VIb) : 5 , _ γ ll. lG 12 A 13 A- , R 15.1_ S _ U 16.1 H 1 _ 3 , (VIa ) 5 , _γiι.α N Ai2 G i2 A i- A ι« R i5.ι_ s _ u ι«.ι H -7_3 , (VIb) 12 in which N, H, Y, R, S, G, A, U and C represent ribonucle and N denotes G, A, U or C H denotes A, C or U R denotes A or G Y denotes C or U and S is an RNA sequence capable of forming a hairpin structure with a length of preferably 6 - 60 and particularlypreferably of 6 - 20 bases. An oligomer with an active centre (IVa) or (IVb) forms th merhead structure shown in Fig. 3 with an RNA substrate c ning a structure of formulae (Via) or (VIb) in which the cleotides are numbered according to the standard nomencla The active centre Z preferably contains no pyrimidine rib cleotides. Z preferably contains no more than six and par larly preferably no more than three ribonucleotides. If the active centre Z contains ribonucleotides, one or s building blocks at positions G s , A 6 , N ? (if N 7 is a purine) A 9 and N 9λ (if N 9A is present and is a purine) are thus pre ably ribonucleotides. The building blocks at positions C 3 , (if N 7 is a pyrimidine) and N 9λ (if N 9λ is present and is a midine) are preferably nucleotide analogue building block particular such building blocks in which W is an optional substituted C : ~C < alkyl, alkenyl, alkoxy or alkenoxy group NH- group. Building blocks are especiallypreferred which only hybridize very weakly with ribonucleotides in the su strate such as those nucleotide analogues which contain a tionally substituted alkyl, alkenyl or alkynyl group acco to formula (II), e.g. an allyl group, at the 2' C atom of ribose. However, 2' -O-nucleotide analogues are on the oth hand also preferred. Specific examples of suitable substi are methoxy, (2-hydroxyethyloxy) , allyl, allyloxy and NH 2 . addition N 7 and N 9λ , if they are present, are selected in s way that a minimum of internal structures can form by int interactions. The preferred nucleobases in the region Z a The minimum stability requirements for a hammerhead structure are three base pairs in stem I and three base pairs in stem III. Although all motifs which fulfil these minimum require¬ ments can be cleaved, the cleavage efficiency depends on the interaction of the actual recognition sequences and on conser¬ ved nucleotides in the active centre. Of the oligomers according to the invention the chimeric oligo¬ nucleotides containing GAAR seem to be less sensitive to inter¬ ferences by undesired interactions and are therefore preferred. RNA substrates of chimeric oligomers with an active centre which has a s .ucture of formulae (Ilia) or (Illb) are prefe¬ rably human cellular transcripts and transcripts of human viru¬ ses. The RNA substrate is particularly preferably selected from the group comprising human interleukin-2 mRNA, human ICAM-1 mRNA, human IGF-β mRNA, human tissue factor pre-mRNA, human protein kinase C-α mRNA, human factor KBF1 mRNA, human 5-li- poxygenase mRNA, human interleukin-8 RNA, human interleukin-5 RNA, human interleukin-1 receptor mRNA, human interleukin-1-α mRNA, human 12-lipoxygenase mRNA, the transcript of the human cytomegalovirus DNA polymerase gene and a transcript of the human papilloma virus type 8. Particularly preferred cleavage motifs for oligomers of the "GAAR" type are located at the following positions of these RNA substrates (the name of the respective sequence in the EMBL Nucleotide Sequence Database 43rd Edition is given in brackets) . human interleukin-2-mRNA (HSIL2R) with C 3 at position 490 and a cleavage after the sequence AUU; human ICAM-1 (intercellular adhesion molecule-1)mRNA (HSI- CAM01) with C 3 at position 1933 and a cleavage after the sequence AUU; human TGF-β (transforming growth factor β)mRNA (HSTGFB1) with C 3 at position 1313 and a cleavage after the sequence CUC; human tissue factor pre-mRNA (HSTFPB) with C 3 at position 6781 and a cleavage after the sequence GUU or with C 3 at position 8831 and a cleavage after the sequence AUC or CUU; human PKC-αt (protein kinase C-α)mRNA (HSPKCA1) with C 3 at position 823 and a cleavage after the sequence UUC or UUU; human factor KBF-1 mRNA (HSNFKB34) with C 3 at position 2619 and a cleavage after the sequence UUA; human 5-lipoxygenase mRNA (HSL0X5A) with C 3 at position 296 and a cleavage after the sequence GUA; human interleukin-8 RNA (HSIL8A) with C 3 at position 4978 and a cleavage after the sequence AUA; human interleukin-5 RNA (HSIL5) with C 3 at position 1896 and a cleavage after the sequence AUU or UUU; human interleukin-1 receptor mRNA (HSIL1RA) with C 3 at position 1485 and a cleavage after the sequence AUC; human interleukin-l-α mRNA (HSIL1ALPH) with C 3 at position 1272 and a cleavage after the sequence CUU; human 12-lipoxygenase mRNA (HSLIPXYG) with C 3 at position 940 and a cleavage after the sequence AUA; transcript of the human cytomegalovirus DNA polymerase gene (HEHS5POL) with C 3 at position 3919 and a cleavage after the sequence UUA; transcript of the human papilloma virus type 8 (PAPPPH8C) with C 3 at position 3221 and a cleavage after the sequence CUU. A particularly preferred example of a cleavage site in a human mRNA is interleukin-2 mRNA. The cleavage site has the nucleo¬ tide sequence shown in SEQ ID NO. 1. An oligomer of the "GAAR" type having the nucleotide sequence shown in SEQ ID NO. 2 is also able to efficiently cleave an appropriate RNA substrate. This oligomer according to the invention can also cleave a 1.6 kb long IL-2 transcript. Human ICAM-1 mRNA is a further particularly preferred example of an RNA substrate which can be cleaved by the chimeric oligo¬ mers of the "GAAR" type. The region which is sensitive for cleavage has the nucleotide sequence shown in SEQ ID NO. 3. An RNA substrate with this sequence can also be efficiently clea¬ ved by an oligomer having the nucleotide sequence shown in SEQ ID NO. 4. Human PKC-α mRNA is a further particularly preferred example of an RNA substrate, which can be cleaved by a chimeric oligomer of the "GAAR" type. The region which is sensitive to cleavage has the nucleotide sequence shown in SEQ ID NO. 9. This sub¬ strate is efficiently cleaved by an oligomer having the nucleo¬ tide sequence shown in SEQ ID. NO. 10. Human interleukin-lα mRNA is a further particularly preferred example of an RNA substrate which can be cleaved by a chimeric oligomer of the "GAAR" type. The region which is sensitive to cleavage has the nucleotide sequence shown in SEQ ID NO. 11. This substrate is efficiently cleaved by an oligomer having the nucleotide sequence shown in SEQ ID NO. 12. Preferred RNA substrates for oligomers according to the inven¬ tion of the "CUGANGA" type are also human cellular transcripts and transcripts of human viruses. The RNA substrate is particu¬ larly preferably selected from the group comprising human in- terleukin-6 mRNA, human multiple drug resistance (MDR-1) mRNA, human monocyte chemotactic protein RNA, human macrophage sca¬ venger receptor type II mRNA, human macrophage scavenger recep¬ tor type I mRNA, human macrophage inflammatory protein-lo; mRNA, human p53 RNA, human jun-B mRNA, human c-jun RNA, human inter- feron γ type II mRNA, human hepatocyte growth factor mRNA, human HER2 mRNA, human Alzheimer's disease amyloid mRNA, human interleu¬ kin-1 mRNA, human interleukin-1 receptor mRNA, human 3-hydroxy- 3-methylglutaryl coenzyme A reductase RNA, human angiotensino- gen mRNA, human angiotensin-convertingenzyme mRNA, human acyl coenzyme A: cholesterol acyltransferase mRNA, human PDGF recep¬ tor mRNA, human TNF receptor mRNA, human TGF β mRNA, human NF- kappa B p65 subunit mRNA, human c-myc RNA, human 12-lipoxyge- nase mRNA, human interleukin-4 RNA, human interleukin-10 mRNA, human basic FGF mRNA, human EGF receptor mRNA, human c-myb mRNA, human c-fos RNA, human bcl-2 mRNA, human bcl-1 mRNA, hu¬ man ICAM-l mRNA, a transcript of human papilloma virus type 11 and transcripts of human papilloma virus type 16 and type 18. Specific examples of suitable substrates are as follows: - human monocyte chemotactic protein RNA (HSMCHEMP) with Y ' at position 2183 and a cleavage after the sequence GUU; - human macrophage scavenger receptor type II RNA (HSPHSR2) with y 11 - 1 at position 833 and a cleavage after the sequence CUC; - human macrophage scavenger receptor type I mRNA (HSPHSR1) with y 11 - 1 at position 813 and a cleavage after the sequence CUC; human macrophage inflammatory protein 1-ce mRNA ( (HHSSRRAANNTTEESS)) wwiitthh AA 1111-"11 aatt position 629 and a cleavage after the sequence CUC; - hhuummaann pp5533 RRNNAA ((HHSSPP5533GG)) with y 11 " 1 at position 19145 and a cleavage after the sequence GUC; human jun-B mRNA (HSJUNB) with y 11 - 1 at and a cleavage after the sequence GUC; human C-jun RNA (HSJUNA) with y 11 - 1 at and a cleavage after the sequence CUC; - human interferon-γ type II mRNA (HSIFNGAMM) with y 11-1 at position 720 and a cleavage after the sequence GUU; - human hepatocyte growth factor mRNA (HSHGF) with Y at position 1197 and a cleavage after the sequence GUC or with Y " at position 1603 and a cleavage after the sequence GUA; - human HER2 (tyrosine kinase receptor) mRNA (HSHER2A) with Y 11'1 at position 2318 and a cleavage after the sequence CUU; - human Alzheimer's disease amyloid mRNA (H3AMY) with Y 11 ' 1 at position 427 and a cleavage after the sequence AUC or with Y ' at position 1288 and a cleavage after the sequence CUA; - human interleukin-1 mRNA (HSIL1) with Y at position 113 and a cleavage after the sequence AUU; human interleukin-1 receptor (IL-1R) mRNA (HSIL1RA) with Y 11 1 at position 84 and a cleavage after the se¬ quence CUC; human 3-hydroxy-3-methylglutarylcoenzyme A reductase mRNA (HSHMGCOB) with y 11'1 at position 257 and a cleavage after the sequence CUC; human angiotensinogen mRNA (HSANG) with y 11"1 at position 2012 and cleavage after the sequence UUC; human angiotensin-convertingenzyme mRNA (HSACE) with Y at position 1818 and a cleavage after the sequence GUA; human acyl coenzyme A: cholesterol acyltransferase mRNA (HSACYLCOA) with y 11 - 1 a t position 374 and a cleavage after the sequence CUA or with y 11'1 at position 830 and a cleavage after the sequence GUA; human PDGF receptor mRNA (HSPDGFRA) with y 11,1 at position 1513 and a cleavage after the sequence CUA; human tumour necrosis factor receptor mRNA (HSTNFRB) with Y at position 502 and a cleavage after the sequence CUU or UUC; human TGF β mRNA (HSTGFBC) with y 11 - 1 at position 545 and a cleavage after the sequence AUC or with Y at position 2428 and a cleavage after the sequence CUC; human NF kappa B p65 subunit mRNA (HSNFKB65A) with Y ' at position 937 and a cleavage after the sequence UUC or with y 11 - 1 at position 2195 and a cleavage after the sequence CUC; human c-myc RNA (HSMYCC) with y 11 - 1 a t position 4336 and a cleavage after the sequence CUU or with Y at position 3799 and a cleavage after the sequence CUA; human c-myc mRNA (HSMYC1) with y 11"1 at position 484 and a cleavage after the sequence CUU; human MDR-1 mRNA (HSMDR1) with y 11 - 1 at position 1513 and a cleavage after the sequence AUA; human 12-lipoxygenase mRNA (HSLIPXYG) with Y ' at position 566 and a cleavage after the sequence CUC; human interleukin-6 mRNA (HSIL6CSF) with y 11-1 at position 13 and a cleavage after the sequence CUA or wwii .tt.hh, Y,Y,11 ' .1 aatt position 902 and a cleavage after the sequence GUA; hhuummaann iinntteerrlleeu' kin-4 RNA (HSIL4A) with y 11 - 1 at position 2500 and a cleavage after the sequence GUC; human interleukin-10 mRNA (HSIL10) with y 11 - 1 at position 1125 and a cleavage after the sequence CUU; human basic FGF mRNA (HSGFBF) with y 11 - 1 at position 260 and a cleavage after the sequence CUA; human EGF receptor mRNA (HSEGFPRE) with y 11 - 1 at position 4778 and a cleavage after the sequence AUA or wwiitthh YY ' aatt position 5508 and a cleavage after the sequence UUC; human c-myb mRNA (HSCMYBLA) with y 11,1 at position 448 and a cleavage after the sequence GUU; human c-fos RNA (HSCFOS) with y 11 - 1 at position 1065 and a cleavage after the sequence GUU or with Y at position 3349 and a cleavage after the sequence UUU; human bcl-2 mRNA (HSBSL2C) with y 11 - 1 at position 5753 and a cleavage after the sequence UUA; human bcl-1 mRNA (HSBCL1) with y 11'1 at position 3725 and a cleavage after the sequence GUC; human ICAM-1 mRNA (HSICAM01) with y 11 - 1 at position 1998 and a cleavage after the sequence GUA; a transcript of the human papilloma virus type 11 (PAPPPH11) with y 11-1 at position 2941 and a cleavage after the sequence AUU; a transcript of the human papilloma virus type 16 (PA16) with Y ' at position 37 and a cleavage after the sequence GUU; a transcript of the human papilloma virus type 16 (PA16) with y 11 ' 1 at position 1126 and a cleavage after the sequence UUA; a transcript of the human papilloma virus type 16 (PA16) with y 11 - 1 at position 1322 and a cleavage after the sequence GUA; a transcript of the human papilloma virus type 16 (PA16) with y 11 - 1 at position 1982 and a cleavage after the sequence AUU; - a transcript of the human papilloma virus type 16 (PA16) with y 11 - 1 at position 6440 and a cleavage after the sequence UUA; - a transcript of the human papilloma virus type 16 LI protein gene (PAPHPU111) with y 11*1 at position 99 and a cleavage after the sequence GUA; - a transcript of the human papilloma virus type 18 (PAPPPH18) with y 11-1 at position 896 and a cleavage after the sequence AUA; transcript of the human papilloma virus type 18 E6 pprrootteeiinn ggeennee ((PPAARRHHPPVVEE66)) wwiitthh yy 1111"-11 at position 172 and a cleavage after the sequence AUA. A particularly preferred RNA substrate for a chimeric oligomer of the "CUGANGA" type is human interleukin-6 mRNA. The region which is sensitive to cleavage has the nucleotide sequence shown in SEQ ID NO. 5. An oligomer having the nucleotide sequence shown in SEQ ID NO. 6 can efficiently cleave such a substrate . Yet a further particularly preferred example of an RNA sub¬ strate which can be cleaved by an oligomer of the "CUGANGA" type is human MDR-1 mRNA. The region which is sensitive to cleavage has the nucleotide sequence shown in SEQ ID NO. 7. An oligomer having the nucleotide sequence shown in SEQ ID No. 8 can efficiently cleave such an RNA substrate. A 1.6 kb long MDR-1 transcript can also be cleaved by this oligomer. A further particularly preferred example of an RNA substrate which can be cleaved by an oligomer of the "CUGANGA" type is human c-jun RNA. The region which is sensitive to cleavage is shown in SEQ ID NO. 13. An oligomer having the nucleotide se¬ quence shown in SEQ ID NO. 14 can cleave such a substrate. A further particularly preferred example of an RNA substrate which can be cleaved by an oligomer of the "CUGANGA" type is human IL-1 receptor mRNA. The region which is sensitive to cleavage is shown in SEQ ID NO. 15. An oligomer having the nu¬ cleotide sequence shown in SEQ ID NO. 16 can efficiently cleave such a substrate . A further particularly preferred example of an RNA substrate which can be cleaved by an oligomer of the "CUGANGA" type is human angiotensinogen mRNA. The region which is sensitive to cleavage is shown in SEQ ID NO. 17. An oligomer having the nu¬ cleotide sequence shown in SEQ ID NO. 18 can efficiently cleave such a substrate. The chimeric oligomers according to the invention have signifi¬ cant advantages compared to the structures of the state of the art. Thus the shortest ribozymes that have been previously used have a minimum length of 15+N+M nucleotides, the active centre being 15 nucleotides long and N and M being the length of the recognition sequences (Benseler et al . , J. Am. Chem. Soc . 115 (1993) , 8483-8484) , and moreover they contain ribonucleotides in at least five positions of the catalytic centre (Paolella et al . , EMBO J. 11 (1992) , 1913-1919 and Yang et al . , Biochemistry 31 (1992) , 5005-5009) . In contrast the oligomers according to the invention only con¬ tain 4+N+M or 5+N+M nucleotides (in the case of the "GAAR" ty¬ pe) or 7+N-t-M or 8+N+M nucleotides (in the case of the "CUGANGA" type) in which N and M are preferably numbers in the range of 5-10. Furthermore they can contain a significantly smaller num¬ ber of natural nucleotides without loss of activity. Due to the reduced length and reduced number of ribonucleotides there are significant advantages with regard to the synthesis of the mo¬ lecules as well as with regard to the stability in vivo. Thus for example the chimeric oligomer described in example 2 of the present application of the "GAAR" type has a half-life in ac¬ tive 10 % human serum of several days. The in vivo stability can be additionally increased by a further reduction in the number of ribonucleotides. In addition the oligomers according to the invention have a very high in vivo activity since the RNA cleavage is promoted by protein factors that are present in the nucleus or cytoplasm of the cell. Examples of such protein factors which can in¬ crease the activity of hammerhead ribozymes are for example the nucleocapsid protein NCp7 of HIV1 (Mϋller et al . , J. Mol . Biol. 242 (1994) , 422-429) and the heterogeneous nuclear ribonucleo- protein Al (Heidenreich et al . , Nucleic Acids Res. 23 (1995) , 2223-2228) . Thus long RNA transcripts can be cleaved highly efficiently within the cell by the oligomers according to the invention. Yet a further advantage of the chimeric oligomers according to the invention is the statistically rare occurrence of cleavage motifs of formulae (Va) or (Vb) , or (Via) or (VIb) (approxima¬ tely one motif/5000 bp) This taken together with the indivi¬ dually selected recognition sequences results in the fact that statistically only the target RNA within the entire human RNA pool is cleaved by the respective chimeric oligomer, whereas only an unproductive binding but no cleavage occurs at other potential binding sites. In addition the oligomers according to the invention do not activate RNAse H due to their low content of deoxyribonucleotides and thus do not cause any unspecific cleavages . A further surprising advantage compared to ribozymes of the state of the art is that in the structures according to the invention the RNA substrate forms a large part of the hammer¬ head structure by which means the dependence of the cleavage activity on the Mg + concentration is positively influenced. Yet a further object of the present invention is a pharmaceuti¬ cal composition that contains one or several chimeric oligomers as the active substance and optionally pharmaceutically accep¬ table auxiliary substances, additives and carriers. This phar¬ maceutical composition is excellently suitable for the produc¬ tion of an agent to specifically inactivate the expression of ger.es in eukaryotes, prokaryotes and viruses especially of hu¬ man genes such as tumour genes or viral genes or RNA molecules in a cell. Further areas of application are the inactivation of the expression of plant genes or insect genes. Thus the oligo¬ mers according to the invention can be used as a drug for hu¬ mans and animals as well as a pesticide for plants. For therapeutic applications the active substance is preferably administered at a concentration of 0.01 to 10,000 μg/kg body weight, particularly preferably of 0.1 to 1000 μg/kg body weight. The administration can for example be carried out by injection, inhalation (e.g. as an aerosol) , as a spray, orally (e.g. as tablets, capsules, coated tablets etc.) , topically or rectally (e.g. as suppositories) . The present invention provides a process for the specific inac¬ tivation of the expression of genes in which an active concen¬ tration of a chimeric oligomer is taken up into a cell (Lyng- stadaas et al . , EMBO J. 14 (1995) 5224-5229) so that the oligo¬ mer specifically cleaves a predetermined RNA molecule which is present in the cell, the cleavage preferably occurring cataly¬ tically. This process can be carried out in vitro on cell cul¬ tures as well as in vivo on living organisms (prokaryotes or eukaryotes such as humans, animals or plants) . Yet a further object of the present invention is the use of the chimeric oligomers as RNA restriction enzymes as well as a rea¬ gent kit for the restriction cleavage of RNA molecules which contains a chimeric oligomer and suitable buffer substances. In this case the oligomer and the buffer substances can be present in the form of solutions, suspensions or solids such as powders or lyophilisates . The reagents can be present together, separa¬ ted from one another or optionally also on a suitable carrier. The oligomers according to the invention can also be used as a diagnostic agent or to identify the function of unknown genes. This invention provides a method of alleviating psoriasis in a subject comprising administering to the subject an effective amount of the chimeric oligomers of this invention capable of cleaving RNAs encoding IL-2, or ICAM-1. This invention also provides a method of alleviating common cold in a subject com¬ prising administering to the subject an effective amount of the chimeric oligomers of this invention capable of cleaving RNAs encoding ICAM-1. This invention further provides a method of alleviating transplant rejection in a subject comprising admi¬ nistering to the subject an effective amount of the chimeric oligomers of this invention capable of cleaving RNAs encoding ICAM-1. Moreover, this invention provides a method of allevia¬ ting Kaposi's sarcoma in a subject comprising administering to the subject an effective amount of chimeric oligomers of this invention capable of cleaving RNAs encoding IL-6. This invention also provides a method of treating human cancer in a subject comprising administering to the subject an effec¬ tive amount of the chimeric oligomers of this invention capable of cleaving RNAs encoding PKC-a. The important role played by PKC-o/ in cancer is described in Dean et al . (Cancer Research 56 (1996) , 3499-3507) and in McKay et al . (Nucleic Acids Research 24 (1996) , 411-417) and in references contained therein. Finally, this invention provides a method of treating hyperten¬ sion in a human subject comprising administering to the subject an effective amount of the chimeric oligomers of this invention capable of cleaving RNAs encoding angiotensinogen. All documents referred to in this application are incorporated in their entirety herein by reference. The invention is additionally elucidated by the following figu¬ res and sequence protocols. They show: Fig. 1 the schematic representation of a hammerhead structure and the corresponding nomenclature; Fig. 2 a hammerhead structure with an oligomer of the "GAAR" type according to the invention; Fig. 3 a hammerhead structure with an oligomer of the "CUGANGA" type according to the invention; Fig. 4a a hammerhead structure which is formed from an inter- leukin-2 mRNA substrate and an oligomer according to the invention, wherein small letters denote ribonu¬ cleotides; Fig. 4b the reaction of the structures shown in Fig. 4a; Fig. 5a a hammerhead structure which is formed from an ICAM-1 mRNA substrate and an oligomer according to the in¬ vention, wherein small letters denote ribonucleoti¬ des; Fig. 5b the reaction of the structures shown in Fig. 5a; Fig. 5c the reaction of the structures shown in Fig. 5a when the chimeric oligomer has 2 ' -allyloxy-nucleotide ana¬ logues in the flanking regions and U is replaced by 2' -allyloxy-thy idine; Fig. 6a a hammerhead structure which is formed from an inter¬ leukin-6 mRNA substrate and an oligomer according to the invention, wherein small letters denote ribonu¬ cleotides; Fig. 6b the reaction of the structures shown in Fig. 6a; Fig. 6c the reaction of the structures shown in Fig. 6a whe¬ reby the substrate is 5' -fluorescently labelled and a variety of chimeric oligomers were tested with diffe¬ rent analogues in the active centre "CUGAUGA"; Fig. 7a a hammerhead structure which is formed from an MDR-1 mRNA substrate and an oligomer according to the in¬ vention, wherein small letters denote ribonucleoti¬ des; Fig. 7b the reaction of the structures shown in Fig. 7a; Fig. 8a a hammerhead structure which is formed from a PKC-α mRNA substrate and an oligomer according to the in¬ vention, wherein small letters denote ribonucleoti¬ des; Fig. 8b the reaction of the structures shown in Fig. 8a; Fig. 9a a hammerhead structure which is formed from an inter¬ leukin-lα mRNA substrate and an oligomer according to the invention, wherein small letters denote ribonu¬ cleotides; Fig. 9b the reaction of the structures shown in Fig. 9a; Fig. 10a a hammerhead structure which is formed from a c-jun RNA substrate and an oligomer according to the inven¬ tion, wherein small letters denote ribonucleotides; Fig. 10b the reaction of the structures shown in Fig. 10a; Fig. 11a a hammerhead structure which is formed from an inter¬ leukin-1 receptor mRNA substrate and an oligomer ac¬ cording to the invention, wherein small letters de¬ note ribonucleotides; Fig. lib the reaction of the structures shown in Fig. 11a; Fig. 12a a hammerhead structure which is formed from an angio- tensinogen mRNA substrate and an oligomer according to the invention, wherein small letters denote ribo¬ nucleotides; Fig. 12b the reaction of the structures shown in Fig. 12a; SEQ ID NO. 1 shows the nucleotide sequence of the interleu- kin-2 RNA substrate shown in Fig. 4a; SEQ ID NO. 2 shows the sequence of the RNA-cleaving oligomer shown in Fig. 4a; SEQ ID NO. 3 shows the nucleotide sequence of the ICAM-1 RNA substrate shown in Fig. 5a; SEQ ID NO. 4 shows the nucleotide sequence of the RNA- cleaving oligomer shown in Fig. 5a; SEQ ID NO. 5 shows the nucleotide sequence of the interleu¬ kin-6 RNA substrate shown in Fig. 6a; SEQ ID NO. 6 shows the nucleotide sequence of the RNA- cleaving oligomer shown in Fig. 6a; SEQ ID NO. 7 shows the nucleotide sequence of the MDR-1 RNA substrate shown in Fig. 7a; SEQ ID NO. 8 shows the nucleotide sequence of the RNA- cleaving substrate shown in Fig. 7a; SEQ ID NO. 9 shows the nucleotide sequence of the PKC-α RNA substrate shown in Fig. 8a; SEQ ID NO. 10 shows the nucleotide sequence of the RNA-clea¬ ving oligomer shown in Fig. 8a; SEQ ID NO. 11 shows the nucleotide sequence of the interleu¬ kin-lα RNA substrate shown in Fig. 9a; SEQ ID NO. 12 shows the nucleotide sequence of the RNA-clea¬ ving oligomer shown in Fig. 9a; SEQ ID NO. 13 shows the nucleotide sequence of the c-jun RNA substrate shown in Fig. 10a; SEQ ID NO. 14 shows the nucleotide sequence of the RNA-clea¬ ving oligomer shown in Fig. 10a; SEQ ID NO. 15 shows the nucleotide sequence of the interleu¬ kin-1 receptor RNA substrate shown in Fig. 11a; SEQ ID NO. 16 shows the nucleotide sequence of the RNA-clea¬ ving oligomer shown in Fig. 11a; SEQ ID NO. 17 shows the nucleotide sequence of the angiotensi- nogen RNA substrate shown in Fig. 12a and SEQ ID NO. 18 shows the nucleotide sequence of the RNA-clea¬ ving oligomer shown in Fig. 12a. In the sequences stated in SEQ ID NO. 1-18 the T at the end of the nucleotide is in each case coupled via its 3' position to the 3' position of the penultimate nucleotide (iT) . The invention is elucidated further by the following examples. Example 1 Cleavage of an interleukin-2 RNA substrate An interleukin-2 RNA substrate having the nucleotide sequence shown in SEQ ID NO. 1 was produced by chemical solid phase syn¬ thesis. Furthermore a chimeric oligomer was synthesized having the nucleotide sequence shown in SEQ ID NO. 2. Synthesis and removal of protecting groups was carried out in the case of the RNA substrate as well as of the chimeric oligomer by means of solid phase techniques (Wincott et al . , Nucleic Acids Res. 23 (1995) , 2677-2684) . Purification was by means of anion-exchange HPLC (Sproat et al . , Nucleosides and Nucleotides 14 (1995) , 255-273) . It was synthesized on an inverse thymidine support (Ortigao et al . , Antisense Research and Development 2 (1992) , 129-146) based either on aminopropyl-modified controlled pore glass or preferably aminomethylpolystyrene (McCollum and An- drus, Tetrahedron Letters 32 (1991), 4069-4072) . Suitable pro¬ tected 2' -methoxynucleoside-3 ' -O-phosphoramiditeswere synthe¬ sized as described by Sproat and Lamond in Oligonucleotides and Analogs - A practical approach, F. Eckstein, publ . (IRL-Press, Oxford, UK, (1991), 49-86) . The 2' -allyloxy-nucleotidemonomers for the solid phase synthesis were also synthesized by standard procedures (Sproat in: Methods in Molecular Biology, Vol. 20: Protocols for Oligonucleotides and Analogs - Synthesis and Pro¬ perties, S. Agrawal, publ./ Humana Press, Totowa, New Jersey, (1993) , 115-141) ) . The sequences of the chimeric oligomer outside of the active centre are composed of nucleotide analogue building blocks which are modified with a methoxy group at the 2'-C atom of the ribose. In the active centre "GAAA" of the oligonucleotide G 12 at position 1 is a ribonucleotide, the residues A 13 and A14 at positions 2 and 3 are 2' -methoxy-modifiednucleotides and A at position 4 is a ribonucleotide. 400 p ol interleukin-2 substrate was reacted with 400 pmol of the oligomer in the presence of 10 mmol/1 MgCl 2 / 50 mmol/1 Tris HCl, 1 mmol/1 EDTA at pH 7.5 and 37°C in a reaction volume of 100 μl . Aliquots were taken at certain times and ad¬ mixed with excess EDTA to prevent further cleavage. The oligo¬ mer mixture present at the different times was then separated by electrophoresis on a 20 % polyacrylamide gel in the presence of 7 M urea and made visible by staining with "stains-all". The result of this reaction is shown in Fig. 4b. This shows that the band (40-mer) allocated to the substrate disappears as the incubation period increases and the intensity of the bands of the cleavage products (31-mer and 9-mer) increases. Similar results to those shown in Fig. 4b were obtained with an 12 oligomer that contains a deoxyguanosine at position G instead of a guanosine. The following two sequences of the active cen- tre Z also led to an effective cleavage of the 40-mer RNA sub¬ strate but with a slightly lower cleavage rate: (i) position G 12 : guanosine; positions A 13 and A14 : 2' -O-methyladenosine; position A ' : 2' -0- (2-hydroxyethyl) -adenosine; (ii) position G : guanosine; posi •t-i■ons A13, A.14 and, A-15.1 : 2_ ,' -0_- (2-hydroxyethyl) -adenosine. Example 2 Cleavage of an ICAM-1 RNA substrate An ICAM-l RNA substrate having the nucleotide sequence shown in SEQ ID NO. 3 and an RNA-cleaving oligomer having the nucleotide sequence shown in SEQ ID NO. 4 were synthesized in an analogous manner to that described in example 1. The nucleotide building blocks used for the oligomer were also the same as those des- cribed in example 1 except that A 13 and A1 were ribonucleoti¬ des . The result of the reaction is shown in Fig. 5b. The reaction conditions were as described in example 1 except that 1 nmol substrate and 100 pmol chimeric oligomer were used. It can be seen that the band of the substrate (43-mer) disappears as the incubation period increases while the intensity of the bands of the products (34-mer and 9-mer) increases. A chimeric oligomer was synthesized in an analogous manner which contained four ribonucleotides in the active centre Z and 2 ' -allyloxy-nucleotides in the flanking regions X and Y. 2'- Allyloxythymidine was used instead of 2' -O-allyl-uridine at the positions in X and Y labelled U. The results of the cleavage of the 43-mer RNA substrate by this oligomer are shown in Fig. 5c. Oligomers based on 2 ' -O-allyloxy-nucleotides are strongly pre¬ ferred over oligomers based on 2' -methoxy-nucleotides (Iribar- ren et al . , Proc . Natl. Acad. Sci . USA 87 (1990) , 7747-7751) especially for therapeutic applications due to their greatly reduced unspecific binding. Example 3 Cleavage of an interleukin-6 RNA substrate An interleukin-6 RNA substrate having the nucleotide sequence shown in SEQ ID NO. 5 and a chimeric oligomer having the nu¬ cleotide sequence shown in SEQ ID NO. 6 were synthesized in an analogous manner to that described in example 1. 2'-Methoxy- modified nucleotides were used in sequences outside the active centre to produce the oligomer. Ribonucleotides were used for the active centre "CUGAUGA". The reaction was carried out as described in example 1. The result is shown in Fig. 6b. The intensity of the bands of the substrate (32-mer) decreases as the incubation period increases and the intensity of the bands of the cleavage products (23-mer and 9-mer) increases. Further reactions were performed as follows: A 5' -fluorescein labelled substrate having the nucleotide sequence shown in SEQ ID NO. 5 was synthesized using a commercially available fluo¬ rescein phosphoramidite monomer, and subjected to cleavage re¬ actions as described above, however using a variety of chimeric oligomers each having the nucleotide sequence shown in SEQ ID NO. 6, all bearing 2' -allyloxy modified nucleotides in regions X and Y but different analogues in the active centre "CUGANGA". The reactions were carried out as described in example 1, ex¬ cept that the chimeric oligomer concentration was 10 μmol/1 and the initial substrate concentration was 2 μmol/1. The time course of the reaction is shown in Fig. 6c using fluorescence detection, so only the full length fluorescein labelled 32mer substrate and the 5' -fluorescein labelled 23mer product 1 are detected. The lanes comprised the following: Lane 1 : Substrate plus chimeric oligomer with 2' -C-allyl-2 ' - deoxycytidine at position C 3 , 2' -amino-2' -deoxyuridine at posi¬ tions U 4 and U 7 and ribonucleotides at positions G s , A 6 , G B , and A 9 in the active centre "CUGANGA". Lane 2 : Substrate plus chimeric oligomer with 2' -C-allyl-2 ' - deoxycytidine at position C 3 , 2' -C-allyl-2' -deoxyuridine at po¬ sitions U 4 and U 7 and ribonucleotides at positions G 5 , A 6 , G e , and A 9 in the active centre "CUGANGA". Lane 3 : Substrate plus chimeric oligomer with 2' -allyloxy-2 ' - deoxycytidine at position C 3 , 2' -C-allyl-2' -deoxyuridine at po¬ sitions U 4 and U 7 and ribonucleotides at positions G 5 , A 6 , G 8 , and A 9 in the active centre "CUGANGA". Lane 4 : Substrate plus chimeric oligomer with 2 ' -allyloxy-2 ' - deoxycytidine at position C 3 , 2 ' -amino-2 ' -deoxyuridine at posi¬ tions U 4 and U 7 and ribonucleotides at positions G 5 , A e , G 8 , and A 9 in the active centre "CUGANGA". Lane 5 : Substrate plus chimeric oligomer containing all ribonu¬ cleotides in the active centre "CUGANGA" . Lane 6 : Substrate only. The chimeric oligomer used in lane 5 is clearly the most effi¬ cient, however, since it contains pyrimidine ribonucleotides in the active centre "CUGANGA" it is less suitable for in vivo use. The chimeric oligomers used in lanes 1 and 4 are somewhat less active, however they contain no pyrimidine ribonucleotides and are thus very well suitable for cell culture and in vivo work. Example 4 Cleavage of a MDR-1 RNA substrate A MDR-1 RNA substrate having the nucleotide sequence shown in SEQ ID NO. 7 and an RNA-cleaving oligomer having the nucleotide sequence shown in SEQ ID NO. 8 were synthesized in an analogous manner to that described in example 1. The oligomer was synthe¬ sized using the nucleotide building blocks stated in example 3. The reaction was carried out as described in example 1. The result is shown in Fig. 7b. Example 5 Synthesis, removal of protecting groups and purification of a chimeric oligomer of the "GAAA" type for cleaving an RNA motif on human ICAM-1 RNA The chimeric oligomer 5' -CCCCT*CgaaaT*CAT*GT*C-iT, in which capital letters denote 2' -allyloxy-nucleotides (T* is 2' -allyl- oxythymidine) , small letters denote ribonucleotides and -iT denotes a 3 ' -3 ' -phosphodiesterbond to deoxythymidine, was syn¬ thesized according to the "trityl-off" technique by a solid phase-β-cyanoethyl phosphoroamidite technique (Sinha et al . , Nucleic Acids Res. 12 (1984) , 4539-4557) on a 1 μmol scale using an inverse thymidine support (Ortigao et al . , Supra) , protected 2' -allyloxy-nucleotidemonomers (Sproat in Methods in Molecular Biology, Supra) and commercially available 2'-0- tert . -butyldimethylsilyl-protected ribonucleotide monomers using a longer coupling period of 15 min. At the end of the synthesis the oligomer was cleaved in the synthesis apparatus from the controlled pore glass or polystyrene suppcrt during a period of 2 h using 2 ml 33 % aqueous ammonia/ethanol (3:1 v/v) . The solution was then kept at 60°C for 6-8 h in a sealed reaction vessel in order to remove all base-labile protecting groups. The reaction vessel was cooled and the solution was evaporated to dryness . The residue was taken up in 300 μl ethanol/water (1:1 v/v) and transferred to a 1.5 ml reaction vessel . Subsequently the solu¬ tion was again lyophilized. Silyl protecting groups were removed by resuspending the resi¬ due in 200 μl dry triethylamine/triethyl-amine- 3 HF/N-methyl- 2-pyrrolidinone (3:4:6 v/v/v) and incubating for 2 h at 60°C (Wincott et al . , Supra) . The chimeric oligomer which had been completely freed of protecting groups was then precipitated by addition of 20 μl 3 M aqueous sterile sodium acetate and sub¬ sequently of 1 ml 1-butanol. The reaction vessel was kept at -20°C for 15 minutes and the precipitate was collected by cen- trifugation for 10 min. The supernatant was carefully removed by decanting, the pellet was taken up in 300 μl 80 % ethanol and the resulting solution was lyophilized. The crude product was firstly analyzed and then purified for 30 min in four aliquots by anion-exchange HPLC on a Dionex Nucleo- pak PA-100 column (9 x 250 mm) at 55°C using a lithium perchlo- rate gradient of 70-230 mM in water/acetonitrile (9:1 v/v) con¬ taining 25 mM Tris pH 7.0. The main peak was collected and the chimeric oligomer was precipitated by addition of 4 volumes of 1-propanol or 2-propanol (Sproat et al . , (1995) Supra) . The precipitate was collected by centrifugation, washed and then dried in a vacuum. The yield of purified product was 2.8 mg . Example 6 Cleavage of a PKC-α RNA substrate A PKC-α RNA substrate having the nucleotide sequence shown in SEQ ID NO. 9 and an RNA-cleaving oligomer having the nucleotide sequence shown in SEQ ID NO. 10 were synthesized in an analo¬ gous manner to that described in example 1. The oligomer was synthesized with 2' -allyloxy-modified nucleotides in the sequences outside the active centre, and with ribonucleotides in the active centre "GAAA" . The reaction was carried out as described in example 1, except that the chimeric oligomer concentration was 10 μmol/1 and the RNA substrate concentration was 2 μmol/1. The result is shown in Fig. 8b. Example 7 Cleavage of an IL-lα RNA substrate An IL-lα RNA substrate having the nucleotide sequence shown in SEQ ID NO. 11 and an RNA-cleaving oligomer having the nucleo¬ tide shown in SEQ ID NO. 12 were synthesized in an analogous manner to that described in example 1. The oligomer was synthe¬ sized with 2 ' -methoxy-modified nucleotides in the sequences outside the active centre, and with ribonucleotides in the ac¬ tive centre "GAAA" . The reaction was carried out as described in example 1, except that the chimeric oligomer concentration was 10 μmol/1 and the RNA substrate concentration was 2 μmol/1. The result is shown in Fig. 9b. Example 8 Cleavage of a c-jun RNA substrate A c-jun RNA substrate having the nucleotide sequence shown in SEQ ID NO. 13 and an RNA-cleaving oligomer having the nucleo¬ tide sequence shown in SEQ ID NO. 14 were synthesized in an analogous manner to that described in example 1. The oligomer was synthesized with 2' -methoxy-modified nucleotides in the sequences outside the active centre, and with ribonucleotides in the active centre "CUGAUGA". The reaction was carried out as described in example 1, except that the chimeric oligomer concentration was 10 μmol/1 and the RNA substrate concentration was 2 μmol/1. The result is shown in Fig. 10b. Example 9 Cleavage of an IL-1 receptor RNA substrate An IL-1 receptor RNA substrate having the nucleotide sequence shown in SEQ ID NO. 15 and an RNA-cleaving oligomer having the nucleotide sequence shown in SEQ ID NO. 16 were synthesized in analogous manner to that described in example 1. The oligomer was synthesized with 2' -allyloxy-modified nucleotides in the sequences outside the active centre, and with ribonucleotides in the active centre "CUGAUGA". The reaction was carried out as described in example 1, except that the chimeric oligomer concentration was 10 μmol/1 and the RNA substrate concentration was 2 μmol/1. The result is shown in Fig. lib. Example 10 Cleavage of an angiotensinogen RNA substrate An angiotensinogen RNA substrate having the nucleotide sequence shown in SEQ ID NO. 17 and an RNA-cleaving oligomer having the nucleotide sequence shown in SEQ ID NO. 18 were synthesized in an analogous manner to that described in example 1. The oligo¬ mer was synthesized with 2' -methoxy-modified nucleotides in the sequences outside the active centre, and with ribonucleoti¬ des in the active centre "CUGAUGA". The reaction was carried out as described in example 1, except that the chimeric oligomer concentration was 10 μmol/1 and the RNA substrate concentration was 2 μmol/1. The result is shown in Fig. 12b. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: VimRx Holdings, Ltd. (B) STREET: 2751 Centerville Road, Suite 210 (C) CITY: Little Falls II, Wilmington (E) COUNTRY: USA (F) POSTAL CODE (ZIP) : Delaware 1980S (ii) TITLE OF INVENTION: Chimeric oligomers having an RNA-cleavage activity (iii) NUMBER OF SEQUENCES: 18 (iv) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.30 (EPO) (vi) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: DE 195 42 404.2 (B) FILING DATE: 14-NOV-1995 (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS : single (D) TOPOLOGY: linear (κi) SEQUENCE DESCRIPTION: SEQ ID NO : 1: AACAACAUUC AUGUGUGAAU AUGCUGAUGA GACAGCAACT 40 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: GUUGCUGUCG AAAUGUUGUU T 21 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 43 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION SEQ ID NO: 3. GACAUGAUUG AUGGAUGUUA AAGUCUAGCC UGAUGAGAGG GGT 43 (2) INFORMATION FOR SEQ ID NO 4 (l) SEQUENCE CHARACTERISTICS: (A) LENGTH 18 base pairs (B) TYPE nucleic acid (C) STRANDEDNESS single (D) TOPOLOGY linear (xi) SEQUENCE DESCRIPTION SEQ ID NO 4 CCCCUCGAAA UCAUGUCT 18 (2) INFORMATION FOR SEQ ID NO 5 (l) SEQUENCE CHARACTERISTICS (A) LENGTH 32 base pairs (B) TYPE nucleic acid (C) STRANDEDNESS single (D) TOPOLOGY linear (xi) SEQUENCE DESCRIPTION SEQ ID NO 5 UACCACUUGA AACAUUUUAU GUAUUAGUUU UT 32 (2) INFORMATION FOR SEQ ID NO 6 (l) SEQUENCE CHARACTERISTICS (A) LENGTH 24 base pairs (B) TYPE nucleic acid (C) STRANDEDNESS single (D) TOPOLOGY linear (xi) SEQUENCE DESCRIPTION SEQ ID NO: 6- AAAACUAACU GAUGAAAGUG GUAT 24 (2) INFORMATION FOR SEQ ID NO. 7 (l) SEQUENCE CHARACTERISTICS (A) LENGTH 31 base pairs (B) TYPE nucleic acid (C) STRANDEDNESS single (D) TOPOLOGY linear (XI) SEQUENCE DESCRIPTION SEQ ID NO 7 GCAGCUUAUG AAAUCUUCAA GAUAAUUGAU T 31 ( 2 ) INFORMATION FOR SEQ ID NO . 8 ( l ) SEQUENCE CHARACTERISTICS (A) LENGTH 23 base pairs (B) TYPE nucleic acid (C) STRANDEDNESS Single (D) TOPOLOGY linear (xi) SEQUENCE DESCRIPTION SEQ ID NO 8 AUCAAUCUGA UGAAUAAGCU GCT 23 (2) INFORMATION FOR SEQ ID NO 9 (l) SEQUENCE CHARACTERISTICS (A) LENGTH 41 base pairs (B) TYPE nucleic acid (C) STRANDEDNESS single (D) TOPOLOGY linear (xi) SEQUENCE DESCRIPTION SEQ ID NO 9 GAUCCCUUUC CUUUGGAGUU UCGGAGCUGA UGAAGAUGCC T 41 (2) INFORMATION FOR SEQ ID NO 10 (l) SEQUENCE CHARACTERISTICS (A) LENGTH 19 base pairs (B) TYPE nucleic acid (C) STRANDEDNESS single (D) TOPOLOGY linear (xi) SEQUENCE DESCRIPTION SEQ ID NO 10 GGCAUCUGAA AAAGGGAUT 19 (2) INFORMATION FOR SEQ ID NO 11 (l) SEQUENCE CHARACTERISTICS (A) LENGTH 39 base pairs (B) TYPE nucleic acid (C) STRANDEDNESS single (D) TOPOLOGY linear (xi) SEQUENCE DESCRIPTION SEQ ID NO 11 UGUUUGCCUU CUACUUUUAA GUUGCUGAUG AACUCUUAT 39 (2) INFORMATION FOR SEQ ID NO 12 (l) SEQUENCE CHARACTERISTICS (A) LENGTH 19 base pairs (B) TYPE nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12: UAAGAGUGAA AGGCAAACT 19 (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: UAGGUGGAGU UGAAAGAGUU AAGAAUGCUC GAUAAAAUCT 40 (2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: UUUUAUCCUG AUGAAACUCC AT 22 (2) INFORMATION FOR SEQ ID NO: 15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 34 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15: AAGAAGAAUA UGAAAGUGUU ACUCAGACUU AUUT 34 (2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: UAAGUCUCUG AUGAAUAUUC UT 22 (2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 39 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: AAUACGUGAA AGAUGCAAGC ACCUGAAUUU CUGUUUGAT 39 (2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: UCAAACACUG AUGAACGUAU UT 22

Claims: Patent Claims Chimeric oligomer having an RNA-cleavage activity which has a structure according to formula (I) : 5'-X-Z-Y-3' (I) in which X and Y represent oligomeric sequences containing building blocks composed of unmodified nucleotides or/and nucleotide analogues and contribute to the formation of a specific hybridisation of the oligomer with an RNA-sub- strate, in which X and Y each contain at least one building block that differs from deoxyribonucleotides and ribonucleotides, wherein Z represents the active centre of the chimeric oligomer having a structure of formulae (Ilia) , (Illb) , (IVa) or (IVb) : 5' -G 12 A A 14 R 15 α -3' (Ilia) 5 , _ N λl2 G 12 A 13 A 14 R 15.1_ 3 , (Illb) 5 ' - C 3 U 4 G s A fi N 7 G B A 9 - 3 ' ( IVa ) 5 ' - C 3 U*G 5 A 6 NG 8 A 9 N 9λ - 3 ' ( IVb ) in which the building blocks of the structures (Ilia) , (Illb) , (IVa) , (IVb) are selected from unmodified nucleoti¬ des or/and nucleotide analogues, in which the building blocks have a structure according to formula (II) : in which B denotes a residue, which is a naturally occur¬ ring nucleobase or a functional equivalent thereof, which is in particular selected from the group comprising adenin- 9-yl (A) , cytosin-1-yl (C) , guanin-9-yl (G) , uracil-1-yl (U) , uracil-5-yl { ψ) hypoxanthin-9-yl (I) , thymin-1-yl (T) , 5-methyl- cytosin-1-yl (5MeC) , 2, 6-diaminopurin-9-yl (Ami- noA) , purin-9-yl (P) , 7-deazaadenin-9-yl (c 7 A) , 7-deaza- guanin-9-yl (c 7 G) , 5-propynylcytosin-l-yl (5-pC) , 5-propy- nyluracil-1-yl (5-pU) , isoguanin-9-yl, 2-aminopurin-9-yl , 6-methyluracil-l-yl, 4-thiouracil-1-yl, 2-pyrimidone-1-yl and quinazoline-2, -dione-1-yl,- V independently denotes an 0, S, NH or CH 2 -group, W independently denotes an H or OH or a straight-chained or branched alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl or alkynyloxy with 1 to 10 C-atoms, which can be optionally substituted by one or several halogen, cyano, amino, carboxy, ester, ether, carboxamide, hydroxyl or/and ercapto groups, or is selected from -C00H, -C0NH 2 , CONHR 1 , CONR'R 2 , -NH 2 , -NHR 1 , -NR'R 2 , -NHCOR 1 , -SH, SR 1 , -F, -0NH 2 , -ONHR 1 , -ONR^ 2 , NHOH, -NHOR 1 , -NR 2 OH and -NR 2 OR 1 , in which R 1 and R 2 independently denote unsubstituted or substituted alkyl, alkenyl or alkynyl groups as defined above, D and E denote residues which together form a phospho¬ diester or phosphorothioate diester bond between adjacent nucleosides or analogues or together form an analogue of an internucleosidic bond, in which the structures (Ilia) or (Illb) do not contain a total of more than two deoxyribonucleotides and the structures (IVa) or (IVb) do not contain a total of more than four deoxyribonucleotides and in which G in each case independently denotes a build¬ ing block according to formula (II) , in which B is guanin-9-yl or a functional equivalent thereof for that particular location in the hammerhead core structure, which is preferably selected from I, c 7 G and isoguanin-9-yl; A in each case independently denotes a build¬ ing block according to formula (II) , in which B is adenin-9-yl or a functional equivalent thereof for that particular location in the hammerhead core structure, which is preferably selected from aminoA, P, c 7 A and 2-aminopurin-9-yl; U in each case independently denotes a build¬ ing block according to formula (II) , in which B is uracil-1-yl or a functional equivalent thereof for that particular location in the hammerhead core structure, which is preferably selected from ψ , T, 5- pU, 6-methyluracil-l-yl, 4-thiouracil-l-yl, 2-pyrimidone-l-yl andquinazoline-2, 4-dione- 1-yl; C in each case independently denotes a build¬ ing block according to formula (II) , in which B is cytosin-1-yl or a functional equivalent thereof for that particular location in the hammerhead core structure, which is preferably selected from 5MeC, 5-pC and 2 -pyrimidone- l-yl ; R in each case independently denotes a build¬ ing block according to formula (II) , in which B independently denotes G or A as defined above; N in each case independently denotes a build¬ ing block according to formula (II) . 2. Oligomer as claimed in claim 1, wherein the regions X and Y do not contain any ribonucleotides at pyrimidine positions. 3. Oligomer as claimed in claim 1 or 2, wherein the regions X and Y do not contain any ribonucleotides. 4. Oligomer as claimed in one of the claims 1-3, wherein the regions X and Y are essentially composed of building blocks having the structure (II) , in which W is in each case independently selected from optionally substituted alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl or alkynyloxy residues with 1 to 10 C atoms. 5. Oligomer as claimed in one of the claims 1-4, wherein the regions X and Y each independently contain 3 to 40 building blocks. 6. Oligomer as claimed in one of the claims 1-5, wherein the active centre Z contains one or several building blocks having the structure (II) , in which W in each case is independently selected from optionally substituted alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl or alkynyloxy residues with 1 to 5 C atoms. 7. Oligomer as claimed in one of the claims 1-6, wherein the building blocks of the active centre Z are linked by phosphodiester bonds. 8. Oligomer as claimed in one of the claims 1-7, wherein the 3' end is protected against exonuclease degradation. 9. Oligomer as claimed in one of the claims 1-8, wherein the active centre Z has the structure (Ilia) or (Illb) and has cleavage activity for an RNA-substrate that contains a structure of formulae (Va) or (Vb) : 5 < -U 16 ' 1 H 17 -S-C 3 U 4 G 5 A 6 N G θ A 9 R 10 - 1 -3' (Va) 5' -U 16 ' 1 H 17 -S-C 3 U 4 G 5 A 6 N 7 G θ A 9 N 9λ R 10 1 -3' (Vb) in which N, H, R, S, G, A, U and C represent ribonucleoti¬ des and N denotes G, A, U or C; H denotes A, C or U; R denotes A or G and S denotes an RNA-sequence capable of forming a hairpin structure. 10. Oligomer as claimed in claim 9, wherein Z has the structure (Ilia) or (Illb) and contains no more than two ribonucleotides. 11. Oligomer as claimed in claim 10, wherein Z has the structure (Ilia) or (Illb) and contains no more than one ribonucleotide. 12. Oligomer as claimed in claim 11, wherein Z has the structure (Ilia) or (Illb) and contains no ribonucleotides and no deoxyribonucleotides. 13. Oligomer as claimed in one of the claims 9-12, wherein G 12 denotes a ribonucleotide, a deoxyribonucleotide or a building block, in which W is a C^C,-alkyl, alkenyl, alkoxy, or alkenyloxy group optionally substituted with OH. 14. Oligomer as claimed in claim 13, wherein is a (2-hydroxyethoxy) residue. 15. Oligomer as claimed in one of the claims 9-14, wherein A 13 , A 14 or/and R 15 x are selected from building blocks, in which is preferably a C : -C 4 -alkyl, alkenyl, alkoxy, or alkenyloxy group, optionally substituted with OH. 16. Oligomer as claimed in claim 15, wherein W is selected from methoxy, (2-hydroxyethoxy) and allyloxy residues . 17. Oligomer as claimed in one of the claims 9-16, wherein the RNA-substrate is selected from the group comprising human interleukin-2 mRNA, human ICAM-1 mRNA, human TGF-β mRNA, human tissue factor pre-mRNA, human protein kinase C- < mRNA, human factor KBF-1 mRNA, human 5-lipoxygenase mRNA, human interleukin-8 RNA, human interleukin-5 RNA, human interleukin-1 receptor mRNA, human interleukin-1-α mRNA, human 12-lipoxygenase mRNA, the transcript of the human cytomegalovirus DNA-polymerase gene and a transcript of the human papilloma virus type 8. 18. Oligomer as claimed in one of the claims 9-17, wherein the RNA-substrate contains a region from human interleukin- 2 mRNA having the nucleotide sequence shown in SEQ ID No. 1. 19. Oligomer as claimed in claim 18, wherein the oligomer contains the nucleotide sequence shown in SEQ ID No. 2. 20. Oligomer as claimed in one of the claims 9-17, wherein the RNA-substrate contains a region from human ICAM-1 mRNA having the nucleotide sequence shown in SEQ ID No. 3. 21. Oligomer as claimed in claim 20, wherein the oligomer contains the nucleotide sequence shown in SEQ ID No. 4. 22. Oligomer as claimed in one of the claims 9-17, wherein the RNA-substrate contains a region from human PKC-α RNA having the nucleotide sequence shown in SEQ ID No. 9. 23. Oligomer as claimed in claim 22, wherein the oligomer contains the sequence shown in SEQ ID No. 10. 24. Oligomer as claimed in one of the claims 9-17, wherein the RNA substrate contains a region from human interleukin- lα mRNA having the nucleotide sequence shown in SEQ ID No 11. 25. Oligomer as claimed in claim 24, wherein the oligomer contains the nucleotide sequence shown in SEQ ID No. 12. 26. Oligomer as claimed in one of the claims 1-8, wherein the catalytic centre Z has the structure (IVa) or (IVb) and exhibits cleavage activity for an RNA-substrate that contains a structure of formulae (Via) or (VIb) : 5 ,_ γ ιι . lG i2 A i3 A κ R i5 ι_s-U 16 1 H 17 -3'l (Via) 5' -Y^^N^G^A^A^R^^-S-U 16 ^^-3' (VIb) in which N, H, Y, R, S, G, A, U and C represent ribonucleo¬ tides and N denotes G, A, U or C, H denotes A, C or U, R denotes A or G Y denotes C or U and S is an RNA sequence capable of forming a hairpin structure. 27. Oligomer as claimed in claim 26, wherein Z has the structure (IVa) or (IVb) and contains no more than six ribonucleotides. 28. Oligomer as claimed in claim 26 or 27, wherein Z contains no pyrimidine ribonucleotides. 29. Oligomer as claimed in one of the claims 26-28, wherein one or several building blocks at the positions G 5 , A 6 , N 7 , G 8 and A 9 are ribonucleotides, in which N 7 is a purine base, in particular A. 30. Oligomer as claimed in one of the claims 26-29, wherein C 3 , U" and N λl2 are selected from building blocks, in which W is an optionally OH-substituted C^C^ alkyl, alkenyl, alkoxy or alkenyloxy group or an NH 2 group. 31. Oligomer as claimed in claim 30, wherein W is selected from methoxy, (2-hydroxyethyloxy) , allyloxy, allyl and NH 2 residues . 32. Oligomer as claimed in one of the claims 26-31, wherein the RNA-substrate is selected from the group comprising human interleukin-6 mRNA, human MDR-1 mRNA, human monocyte chemotactic protein RNA, human macrophage scavenger receptor type II mRNA, human macrophage scavenger receptor type 1 mRNA, human macrophage-inflammatory protein-lα mRNA, human p53 RNA, human jun-B mRNA, human c-jun RNA, human interferon-γ type II mRNA, human hepatocyte growth factor mRNA, human HER2 mRNA, human Alzheimer's disease amyloid mRNA, human interleukin-1 mRNA, human interleukin-1 receptor mRNA, human 3-hydroxy-3-methylglutaryl coenzyme A reductase RNA, human angiotensinogen mRNA, human angioten- sin-converting enzyme mRNA, human acyl-coenzyme A: chole¬ sterol acyltransferase mRNA, human PDGF receptor mRNA, human TNF receptor mRNA, human TGF β mRNA, human NF-kappa B p65 subunit mRNA, human c-myc RNA, human 12-lipoxygenase mRNA, human interleukin-4 RNA, human interleukin-10 mRNA, human basic FGF mRNA, human EGF-receptor mRNA, human c-myb mRNA, human c-fos RNA, human bcl-2 mRNA, human bcl-1 mRNA, human ICAM-1 mRNA, a transcript of human papilloma virus type 11 and transcripts of human papilloma virus type 16 and type 18 . 33. Oligomer as claimed in one of the claims 26-32, wherein the RNA-substrate contains a region from human interleukin- 6 mRNA having the nucleotide sequence shown in SEQ ID No. 5. 34. Oligomer as claimed in claim 33, wherein the oligomer contains the nucleotide sequence shown in SEQ ID No. 6. 35. Oligomer as claimed in one of the claims 26-32, wherein the RNA substrate contains a region from human MDR-1 mRNA having the nucleotide sequence shown in SEQ ID No. 7. 36. Oligomer as claimed in claim 35, wherein the oligomer contains the nucleotide sequence shown in SEQ ID No. 8. 37. Oligomer as claimed in one of the claims 26-32, wherein the RNA substrate contains a region from c-jun RNA having the nucleotide sequence shown in SEQ ID No. 13. 38. Oligomer as claimed in claim 37, wherein the oligomer contains the nucleotide sequence shown in SEQ ID No. 14. 39. Oligomer as claimed in one of the claims 26-32, wherein the RNA substrate contains a region from human interleukin- 1 receptor mRNA having the nucleotide sequence shown in SEQ ID No. 15. 40. Oligomer as claimed in claim 39, wherein the oligomer contains the nucleotide sequence shown in SEQ ID No. 16. 41. Oligomer as claimed in one of the claims 26-32, wherein the RNA substrate contains a region from human angiotensi¬ nogen RNA having the nucleotide sequence shown in SEQ ID No. 17. 42. Oligomer as claimed in claim 41, wherein the oligomer contains the nucleotide sequence shown in SEQ ID No. 18. 43. Oligomer as claimed in one of the claims 1-42, wherein it is linked to a prosthetic group. 44. Pharmaceutical composition that contains one or several chimeric oligomers as claimed in one of the claims 1-43 as the active substance and optionally pharmaceutically acceptable auxiliary substances, additives and carriers. 45. Use of a chimeric oligomer as claimed in one of the claims 1-43 or a pharmaceutical composition as claimed in claim 44 to produce an agent for the specific inactivation of the expression of genes in eukaryotes, prokaryotes and viruses. 46. Use as claimed in claim 45 for the specific inactivation of the expression of human genes in a cell. 47. Use as claimed in claim 46 for the specific inactivation of the expression of tumor genes . 48. Use as claimed in claim 45 for the specific inactivation of the expression of viral genes or RNA molecules in a cell. 49. Use as claimed in claim 45 for the specific inactivation of the expression of plant genes. 50. Use as claimed in one of the claims 45-49, wherein the active substance is administered at a concentration of 0.01 to 10,000 μg/kg body weight. 51. Use as claimed in one of the claims 45-50, wherein the active substance is administered by injection, inhala¬ tion, as a spray, orally, topically or rectally. 52. Process for the specific inactivation of the expression of genes, wherein a chimeric oligomer as claimed in one of the claims 1-43 is introduced into a cell in an active concentration so that the oligomer specifically cleaves a predetermined RNA mole¬ cule present in the cell. 53. Process as claimed in claim 52, wherein the cleavage occurs catalytically. 54. Use of a chimeric oligomer as claimed in one of the claims 1-43 as an RNA restriction enzyme. 55. A kit for the restriction cleavage of RNA molecules, wherein it contains a chimeric oligomer as claimed in one of the claims 1-43 and suitable buffer substances. 56. Use of a chimeric oligomer as claimed in one of the claims 1-43 as a diagnostic agent. 57. Use of a chimeric oligomer as claimed in one of the claims 1-43 to identify the function of unknown genes. 58. A method of alleviating psoriasis in a subject comprising administering to the subject an effective amount of an oligomer selected from the group consisting of the oligo¬ mers of claims 1-16 and 26-31, wherein the RNA substrate is an IL-2 or ICAM--1 RNA. 59. A method of alleviating common cold in a subject comprising administering to the subject an effective amount of an oligomer selected from the group consisting of the oligo¬ mers of claims 1-16 and 26-31, wherein the RNA substrate is an ICAM-1 RNA. 60. A method of alleviating transplant rejection in a subject comprising administering to the subject an effective amount of an oligomer selected from the group consisting of the oligomers of claims 1-16 and 26-31, wherein the RNA substrate is an ICAM-1 RNA. 61. A method of alleviating Kaposi's sarcoma in a subject comprising administering to the subject an effective amount of an oligomer selected from the group consisting of the oligomers of claims 1-16 and 26-31, wherein the RNA substrate is an I -6 RNA. 62. A method of treating cancer in a subject comprising administering to the subject an effective amount of an oligomer selected from the group consisting of the oligo¬ mers of claims 1-16 and 26-31, wherein the RNA substrate is a PKC-α RNA. 63. A method of treating hypertension in a subject comprising administering to the subject an effective amount of an oligomer selected from the group consisting of the oligo¬ mers of claims 1-16 and 26-31, wherein the RNA substrate is an angiotensinogen RNA.

Inventors: LUDWIG JANOS, SPROAT BRIAN, LUDWIG, JANOS, SPROAT, BRIAN
Applicants: LUDWIG JANOS, SPROAT BRIAN, VIMRX HOLDINGS LTD, LUDWIG, JANOS, SPROAT, BRIAN, VIMRX HOLDINGS, LTD.
Application year: 1996
Main classification: C12N15
IPC codes: A61K31, A61K38, A61K48, A61P9, A61P17, A61P31, A61P35, A61P37, C12N9, C12N15, C12Q1