2′-branched nucleosides and
View Patent ↗The present invention discloses a method for the treatment of Flaviviridae infection that includes the administration of a 2′-branched nucleoside, or a pharmaceutically acceptable prodrug and/or salt thereof, to a human in need of therapy in combination or alternation with a drug that directly or indirectly induces a mutation in the viral genome at a location other than a mutation of a nucleotide that results in a change from serine to a different amino acid in the highly conserved consensus sequence, XRX S GXXXT (SEQ ID NO: 63), of domain B of the RNA polymerase region, or is associated with such a mutation. The invention also includes a method to detect a mutant strain of Flaviviridae and a method for its treatment.
1. An isolated oligonucleotide probe at least 10 nucleotides in length that hybridizes to a subsequence of SEQ ID NO:32 comprising position 31, wherein the oligonucleotide probe comprises a sequence that is complementary to the ACC at positions 30 to 32 of SEQ ID NO:32.
2. The probe of claim 1 , wherein the oligonucleotide probe has 0, 1, 2, 3, 4, 5, or 6 mismatches in complementarity to one of the nucleotide sequences set forth in SEQ ID NOS: 33-62.
3. A method for identifying a drug resistant hepatitis C virus comprising contacting the oligonucleotide probe of claim 1 with a nucleic acid of said drug resistant hepatitis C virus under conditions wherein said probe hybridizes to said nucleic acid, and wherein said drug resistant hepatitis C virus is identified.
4. The method of claim 3 , wherein the viral resistance is to a 2′-branched nucleoside.
5. The method of claim 4 , wherein the viral resistance is to a 2′-C-methyl-branched nucleoside.
6. A method for identifying a drug resistant hepatitis C virus comprising contacting the oligonucleotide probe of claim 2 with a nucleic acid of said drug resistant hepatitis C virus under conditions wherein said probe hybridizes to said nucleic acid, and wherein said drug resistant hepatitis C virus is identified.
7. The method of claim 6 , wherein the viral resistance is to a 2′-branched nucleoside.
8. The method of claim 7 , wherein the viral resistance is to a 2′-C-methyl-branched nucleoside.
9. An isolated oligonucleotide probe at least 14 nucleotides in length that hybridizes to a subsequence of SEQ ID NO:32 comprising position 31, wherein the oligonucleotide probe comprises a sequence that is complementary to the ACC at positions 30 to 32 of SEQ ID NO:32.
10. The probe of claim 9 , wherein the oligonucleotide probe has 0, 1, 2, 3, 4, 5, or 6 mismatches in complementarity to one of the nucleotide sequences set forth in SEQ ID NOS: 33-62.
11. A method for identifying a drug resistant hepatitis C virus comprising contacting the oligonucleotide probe of claim 9 with a nucleic acid of said drug resistant hepatitis C virus under conditions wherein said probe hybridizes to said nucleic acid, and wherein said drug resistant hepatitis C virus is identified.
12. The method of claim 11 , wherein the viral resistance is to a 2′-branched nucleoside.
13. The method of claim 12 , wherein the viral resistance is to a 2′-C-methyl-branched nucleoside.
14. A method for identifying a drug resistant hepatitis C virus comprising contacting the oligonucleotide probe of claim 10 with a nucleic acid of said drug resistant hepatitis C virus under conditions wherein said probe hybridizes to said nucleic acid, and wherein said drug resistant hepatitis C virus is identified.
15. The method of claim 14 , wherein the viral resistance is to a 2′-branched nucleoside.
16. The method of claim 15 , wherein the viral resistance is to a 2′-C-methyl-branched nucleoside.
17. An isolated oligonucleotide probe about 10 to 30 nucleotides in length that hybridizes to a subsequence of SEQ ID NO:32 comprising position 31, wherein the oligonucleotide probe comprises a sequence that is complementary to the ACC at positions 30 to 32 of SEQ ID NO:32.
18. The probe of claim 17 , wherein the oligonucleotide probe has 0, 1, 2, 3, 4, 5, or 6 mismatches in complementarity to one of the nucleotide sequences set forth in SEQ ID NOS: 33-62.
19. A method for identifying a drug resistant hepatitis C virus comprising contacting the oligonucleotide probe of claim 17 with a nucleic acid of said drug resistant hepatitis C virus under conditions wherein said probe hybridizes to said nucleic acid, and wherein said drug resistant hepatitis C virus is identified.
20. The method of claim 19 , wherein the viral resistance is to a 2′-branched nucleoside.
21. The method of claim 20 , wherein the viral resistance is to a 2′-C-methyl-branched nucleoside.
22. A method for identifying a drug resistant hepatitis C virus comprising contacting the oligonucleotide probe of claim 18 with a nucleic acid of said drug resistant hepatitis C virus under conditions wherein said probe hybridizes to said nucleic acid, and wherein said drug resistant hepatitis C virus is identified.
23. The method of claim 22 , wherein the viral resistance is to a 2′-branched nucleoside.
24. The method of claim 23 , wherein the viral resistance is to a 2′-C-methyl-branched nucleoside.