Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1995-10-23
2001-02-06
Robinson, Douglas W. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024500, C536S025500, C514S04400A, C435S006120
Reexamination Certificate
active
06184369
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of oligonucleotide chemistry and anti-viral pharmacotherapy. More specifically, the present invention relates to novel guanosine-rich oligonucleotides and their use as novel anti-viral agents.
2. Description of the Related Art
Previously, it was believed that “antisense” oligonucleotides inhibit viruses by interfering with protein translation via an RNA:DNA duplex structure. More recent research, however, indicates a variety of possible mechanisms by which oligonucleotides inhibit viral infections. For example, oligodeoxycytidine (poly SdC) inhibits HIV-1. Marshall et al., PNAS (1992) 89:6265-6269, discussed the potential mechanism (competitive inhibition) by which oligodeoxycytidine directly inhibits viral reverse transcriptase. Poly SdC also inhibited AMV reverse transcriptase and Pol I (Klenow fragment) and polymerase &agr;, &bgr; and &ggr;. Previously, Matsukura et al., PNAS (1987) 84:7706-7710, used a similar phosphorothioate derivative of oligodeoxycytidine to demonstrate inhibition of HIV-1 in culture. Marshall and Caruthers, Science (1993) 259:1564-1569, reported the use of diphosphorothioate oligonucleotides, e.g., antisense specific, random nucleotide combinations and oligodeoxycytidine against HIV-1. In all cases, the mechanism of action was attributed to a direct inhibition of HIV-1 reverse transcriptase. Other potential mechanisms of anti-viral action of oligonucleotides were postulated by Boiziau et al., PNAS (1992) 89:768-772, e.g., promotion of RNAse H activity and inhibition of reverse transcriptase initiating cDNA synthesis. In addition, Goa et al., Molecular Pharmacology (1992) 41:223-229 reported that phosphorothioate oligonucleotides inhibit human DNA polymerases and RNAse H, and the adsorption or penetration of the virus into cells. Iyer et al., Nucleic Acids Research (1990) 18:2855-2859 report that if a base was removed from an anti-sense polynucleotide forming an abasic site, the compound did not lose its activity which argues against the need for the formation of an RNA:DNA antisense mediated hybrid for anti-viral activity. Stein et al. have characterized the interaction of poly SdC with the V3 loop of HIV-1 gp120, and postulated that the specific interaction of poly SdC with the HIV-1 V3 loop may be a mechanism by which an oligonucleotide could inhibit HIV-1 in vivo.
It is known that synthetic oligonucleotides may be designed which are capable of binding to duplex DNA to form triplex DNA. See U.S. Pat. No. 5,176,996 Hogan & Kessler issued Jan. 5, 1993. This application describes a method for making synthetic guanosine-rich oligonucleotides which are targeted to specific sequences in duplex DNA and which form colinear triplexes by binding to the major groove of the DNA duplex.
SUMMARY OF THE INVENTION
In one embodiment of the present invention, there is provided a method of treating a pathophysiological state caused by a virus, comprising the step of administering a pharmacological dose of an oligonucleotide, said dose being sufficient to inhibit production of said virus, wherein said oligonucleotide contains a high percentage of guanosine bases. In a particular embodiment, the oligonucleotide has a three dimensional structure and this structure is stabilized by guanosine tetrads. In a further embodiment, the oligonucleotide has two or more runs of two contiguous deoxyguanosines.
In another embodiment of the present invention, there is provided a method of treating a pathophysiological state caused by a herpes simplex virus, comprising the step of administering a pharmacological dose of an oligonucleotide, said dose being sufficient to inhibit the replication of said virus, wherein said oligonucleotide contains a high percentage of guanosine bases. In a particular embodiment, the oligonucleotide has a three dimensional structure and this structure is stabilized by guanosine tetrads.
In a further embodiment, the oligonucleotide has two or more runs of two contiguous deoxyguanosines.
In yet another embodiment of the present invention, there is provided a method of treating a pathophysiological state caused by human immunodeficiency viruses, comprising the step of administering a pharmacological dose of an oligonucleotide, said dose being sufficient to inhibit the replication of said virus, wherein said oligonucleotide contains a high percentage of guanosine bases. In a particular embodiment, the oligonucleotide has a three dimensional structure and this structure is stabilized by guanosine tetrads. In a further embodiment, the oligonucleotide has two or more runs of two contiguous deoxyguanosines.
In still yet another embodiment of the present invention, there is provided a method of treating a pathophysiological state caused by human papilloma virus, comprising the step of administering a pharmacological dose of an oligonucleotide, said dose being sufficient to inhibit the replication of said virus, wherein said oligonucleotide contains a high percentage of guanosine bases. In a particular embodiment, the oligonucleotide has a three dimensional structure and this structure is stabilized by guanosine tetrads. In a further embodiment, the oligonucleotide has two or more runs of two contiguous deoxyguanosines.
In still yet another embodiment of the present invention, there is provided a method of treating a pathophysiological state caused by human cytomegalovirus, comprising the step of administering a pharmacological dose of an oligonucleotide, said dose being sufficient to inhibit the replication of said virus, wherein said oligonucleotide contains a high percentage of guanosine bases. In a particular embodiment, the oligonucleotide has a three dimensional structure and this structure is stabilized by guanosine tetrads. In a further embodiment, the oligonucleotide has two or more runs of two contiguous deoxyguanosines.
In still yet another embodiment of the present invention, there is provided a method of treating a pathophysiological state caused by adenovirus, comprising the step of administering a pharmacological dose of a oligonucleotide, said dose being sufficient to inhibit the replication of said virus, wherein said oligonucleotide contains a high percentage of guanosine bases. In a particular embodiment, the oligonucleotide has a three dimensional structure and this structure is stabilized by guanosine tetrads. In a further embodiment, the oligonucleotide has two or more runs of two contiguous deoxyguanosines.
In still yet another embodiment of the present invention, there is provided a method of treating a pathophysiological state caused by hepatitis B virus, comprising the step of administering a pharmacological dose of a oligonucleotide, said dose being sufficient to inhibit the replication of said virus, wherein said oligonucleotide contains a high percentage of guanosine bases. In a particular embodiment, the oligonucleotide has a three dimensional structure and this structure is stabilized by guanosine tetrads. In a further embodiment, the oligonucleotide has two or more runs of two contiguous deoxyguanosines.
In still yet another embodiment of the present invention, there is provided a guanosine-rich oligonucleotide having a three dimensional structure, wherein the three dimensional structure is stabilized by guanosine tetrads or at least two runs of two contiguous deoxyguanosines and wherein these oligonucleotides exhibit anti-viral activity.
In a further embodiment, the oligonucleotides of the present invention have partially or fully phosphorothioated internucleoside linkages (backbones) or other chemical modifications.
In a further embodiment, the oligonucleotides of the present invention have chemically modified or unnatural (synthetic) bases.
REFERENCES:
patent: 3687808 (1972-08-01), Merigan et al.
patent: 4388306 (1983-06-01), Field et al.
patent: 4981957 (1991-01-01), LeBleu et al.
patent: 5075217 (1991-12-01), Weber
patent: 5176996 (1993-01-01), Hogan et al.
patent: 5334711 (1994-08-01), Sproat et al.
patent: 5397702 (1995
Fennewald Susan
Hogan Michael E.
Oiwana Joshua O.
Rando Robert F.
Zendegui Joseph G.
Aronex Pharmaceuticals, Inc.
Crane Eric
McDaniel & Associates
Robinson Douglas W.
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