Treatment of viral infections by modulation of host cell metabolic pathways
View Patent ↗Alterations of certain metabolite concentrations and fluxes that occur in response to viral infection are described. Host cell enzymes in the involved metabolic pathways are selected as targets for intervention; i.e., to restore metabolic flux to disadvantage viral replication, or to further derange metabolic flux resulting in “suicide” of viral-infected cells (but not uninfected cells) to limit viral propagation. While any of the enzymes in the relevant metabolic pathway can be selected, pivotal enzymes at key control points in these metabolic pathways are preferred as candidate antiviral drug targets. Inhibitors of these enzymes are used to reverse, or redirect, the effects of the viral infection. Drug candidates are tested for antiviral activity using screening assays in vitro and host cells, and in animal models. Animal models are then used to test efficacy of candidate compounds in preventing and treating viral infections. Antiviral activity of enzyme inhibitors is demonstrated.
1. A method for treating or impeding the onset of infection by a herpesvirus, comprising administering to a subject in need thereof a therapeutically effective amount of the Formula XXXII:
or a prodrug thereof, or a pharmaceutically acceptable salt or ester of said compound or prodrug, wherein:
(a) X is —O(C 5 -C 20 )alkyl, —O(C 5 -C 20 )alkenyl, or —S(C 5 -C 20 )alkyl; and
(b) Y is O, or S; and
wherein the prodrug comprises a biohydrolyzable ester, a biohydrolyzable amine, or biohydrolyzable carbonate.
2. The method of claim 1 , wherein X is —O(C 10 -C 20 )alkyl or —O(C 10 -C 20 )alkenyl.
3. The method of claim 1 , wherein Y is O.
4. The method of claim 1 , wherein the compound of the Formula XXXII is 5-(tetradecyloxy)-2-furoic acid (TOFA).
5. The method of claim 1 , wherein the compound of Formula XXXII has the structure:
6. The method of claim 1 , wherein the compound of Formula XXXII is administered at a dose of about 500 mg/day to about 1000 mg/day.
7. The method of claim 1 , wherein the compound of Formula XXXII is administered at a dose of about 1000 mg/day to about 1500 mg/day.
8. The method of claim 1 , wherein the compound of Formula XXXII is administered at a dose of about 1000 mg/day to about 1500 mg/day.
9. The method of claim 1 , wherein the compound of Formula XXXII is administered at a dose of about 1500 mg/day.
10. The method of any one of claims 1 to 9 , wherein the method is for treating an infection by a herpesvirus.
11. The method of any one of claims 1 to 9 , wherein the compound is administered to the subject prophylactically.
12. The method of any one of claims 1 to 9 , wherein the compound is co-administered with a cholesterol biosynthesis inhibitor, or pharmaceutically acceptable salt of said inhibitor.
13. The method of claim 12 , wherein the cholesterol biosynthesis inhibitor is an 3-hydroxy-3-methyl-glutaryl-CoA (HMGCoA) reductase inhibitor.
14. The method of claim 13 , wherein the HMG-CoA reductase inhibitor is mevastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, or itavastatin.
15. The method of any one of claims 1 to 9 , wherein the compound is co-administered with foscarnet or a nucleoside analog.
16. The method of claim 15 , wherein the nucleoside analog is gancyclovir, cidofovir, acyclovir, famciclovir, penciclovir, valaciclovir, trifluridine, idoxuridine, vidarabine, ribavirin.
17. A method for treating or impeding the onset of infection by an influenza virus, comprising administering to a subject in need thereof a therapeutically effective amount of the Formula XXXII:
or a prodrug thereof, or a pharmaceutically acceptable salt or ester of said compound or prodrug, wherein:
(c) X is —O(C 5 -C 20 )alkyl, —O(C 5 -C 20 )alkenyl, or —S(C 5 -C 20 )alkyl; and
(d) Y is O, or S; and
wherein the prodrug comprises a biohydrolyzable ester, a biohydrolyzable amine, or biohydrolyzable carbonate.
18. The method of claim 17 , wherein X is —O(C 10 -C 20 )alkyl or —O(C 10 -C 20 )alkenyl.
19. The method of claim 17 , wherein Y is O.
20. The method of claim 17 , wherein the compound of the Formula XXXII is 5-(tetradecyloxy)-2-furoic acid (TOFA).
21. The method of claim 17 , wherein the compound of Formula XXXII has the structure:
22. The method of claim 17 , wherein the compound of Formula XXXII is administered at a dose of about 500 mg/day to about 1000 mg/day.
23. The method of claim 17 , wherein the compound of Formula XXXII is administered at a dose of about 1000 mg/day to about 1500 mg/day.
24. The method of claim 17 , wherein the compound of Formula XXXII is administered at a dose of about 1000 mg/day to about 1500 mg/day.
25. The method of claim 17 , wherein the compound of Formula XXXII is administered at a dose of about 1500 mg/day.
26. The method of any one of claims 17 to 25 , wherein the method is for treating an infection by an influenza virus.
27. The method of any one of claims 17 to 25 , wherein the compound is administered to the subject prophylactically.
28. The method of any one of claims 17 to 25 , wherein the compound is co-administered with a cholesterol biosynthesis inhibitor, or pharmaceutically acceptable salt of said inhibitor.
29. The method of claim 28 , wherein the cholesterol biosynthesis inhibitor is an 3-hydroxy-3-methyl-glutaryl-CoA (HMGCoA) reductase inhibitor.
30. The method of claim 29 , wherein the HMG-CoA reductase inhibitor is mevastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, or itavastatin.
31. The method of any one of claims 17 to 25 , wherein the compound is co-administered with amantadine, oseltamavir, rimantadine, or zanamivir.