Methods and compositions for inhibition of polymerase
The present invention is directed to methods and compositions for inhibition of viral nucleic acid polymerases, such as RNA and DNA polymerases, and methods and compositions that are useful for treating viral infections in subjects. The methods comprise administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, or a composition comprising a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. The composition or method may optionally comprise one or more additional anti-viral agents.
1. A method for inhibition of RNA viral polymerase in a subject, comprising administering to said subject a therapeutically effective amount of a compound of formula (I)
or pharmaceutically acceptable salt or hydrate thereof; and the RNA viral polymerase is:
(a) a polymerase selected from the group consisting of orthomyxoviridae, paramyxoviridae, arenaviridae, bunyaviridae, flaviviridae, filoviridae, togaviridae, picornaviridae, and coronaviridae viral polymerases; or
(b) a polymerase selected from the group consisting of rhinovirus, polio, measles, Ebola, Coxsackie, West Nile, yellow fever, Dengue fever, influenza A, influenza B, lassa, lymphocytic choriomeningitis, Junin, Machupo, guanarito, hantavirus, Rift Valley Fever, La Crosse, California encephalitis, Crimean-Congo, Marburg, Japanese Encephalitis, Kyasanur Forest, Venezuelan equine encephalitis, Eastern equine encephalitis, Western equine encephalitis, severe acute respiratory syndrome (SARS), parainfluenza, respiratory syncytial, Punta Toro Tacaribe and Pichinde viral polymerases.
2. The method of claim 1 , wherein a second RNA viral polymerase is inhibited, and the second RNA viral polymerase is:
(a) a polymerase selected from the group consisting of orthomyxoviridae, paramyxoviridae, arenaviridae, bunyaviridae, flaviviridae, filoviridae, togaviridae, picornaviridae, and coronaviridae viral polymerases; or
(b) a polymerase selected from the group consisting of influenza A, influenza B, parainfluenza, respiratory syncytial, rhinovirus, Junin, Pichinde, Rift Valley Fever, Dengue fever, measles, yellow fever, Tacaribe, Venezuelan equine encephalitis, West Nile, and SARS-CoV viral polymerases.
3. The method of claim 2 , wherein the second RNA viral polymerase is selected from the group consisting of influenza A, influenza B, parainfluenza, respiratory syncytial, rhinovirus, Junin, Pichinde, Rift Valley Fever, Dengue fever, measles, yellow fever, Tacaribe, Venezuelan equine encephalitis, West Nile, and SARS-CoV viral polymerases.
4. The method of claim 1 , wherein the RNA viral polymerase is selected from the group consisting of rhinovirus, polio, measles, Ebola, Coxsackie, West Nile, yellow fever, Dengue fever, influenza A, influenza B, lassa, lymphocytic choriomeningitis, Junin, Machupo, guanarito, hantavirus, Rift Valley Fever, La Crosse, California encephalitis, Crimean-Congo, Marburg, Japanese Encephalitis, Kyasanur Forest, Venezuelan equine encephalitis, Eastern equine encephalitis, Western equine encephalitis, severe acute respiratory syndrome (SARS), parainfluenza, respiratory syncytial, Punta Toro, Tacaribe and Pichinde viral polymerases.
5. The method of claim 4 , wherein the RNA viral polymerase is a polymerase selected from the group consisting of Dengue fever, influenza A, influenza B, Junin, measles, parainfluenza, Pichinde, Punta Toro, respiratory syncytial, rhinovirus, Rift Valley Fever, SARS, Tacaribe, Venezuelan equine encephalitis, West Nile, and yellow fever viral polymerases.
6. The method of claim 4 , wherein the RNA viral polymerase is a polymerase selected from the group consisting of Ebola, yellow fever, Marburg, influenza A and influenza B viral polymerases.
7. The method of claim 4 , wherein the RNA viral polymerase is Ebola viral polymerase.
8. The method of claim 4 , wherein the RNA viral polymerase is measles viral polymerase.
9. The method of claim 4 , wherein the RNA viral polymerase is yellow fever viral polymerase.
10. The method of claim 4 , wherein the RNA viral polymerase is influenza A or influenza B viral polymerase.
11. The method of claim 4 , wherein the RNA viral polymerase is Marburg viral polymerase.
12. The method of claim 4 , wherein the RNA viral polymerase is West Nile viral polymerase.
13. The method of claim 4 , wherein the RNA viral polymerase is Dengue fever viral polymerase.
14. The method of claim 4 , wherein the RNA viral polymerase is Rift Valley Fever viral polymerase.
15. The method of claim 1 , wherein the subject is a mammal.
16. The method of claim 1 , wherein the subject is a human.
17. The method of claim 1 , further comprising administration of an additional anti-viral agent.
18. The method of claim 17 , wherein the additional anti-viral agent is selected from the group consisting of laninamivir, oseltamivir, zanamivir, and peramivir.
19. The method of claim 17 , wherein the additional anti-viral agent is peramivir.
20. The method of claim 1 , wherein administration of said compound is selected from the group consisting of intravenous, interperitoneal, intramuscular, and oral administration.