Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro

• Published in: Antiviral chemistry & chemotherapy 2001-11, Vol.12 (6), p.327-335
• Main Authors: Smee, Donald F, Bray, Mike, Huggins, John W
• Format: Article
• Language: English
• Subjects: 3T3 Cells; 6-Azauridine; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral activity; Antiviral agents; Antiviral Agents - pharmacology; Biological and medical sciences; Cercopithecus aethiops; Cidofovir; Cowpox; Cytotoxicity; Guanosine; Guanosine triphosphate; Guanosine Triphosphate - metabolism; IMP Dehydrogenase - metabolism; Inhibitory Concentration 50; Inosine monophosphate; Intracellular; Kidneys; Medical sciences; Mice; Mode of action; Mpox; Mycophenolic acid; Mycophenolic Acid - pharmacology; Orthopoxvirus; Orthopoxvirus - drug effects; Orthopoxvirus - physiology; Pharmacology. Drug treatments; Ribavirin; Ribavirin - metabolism; Ribavirin - pharmacology; Time Factors; Vaccinia; Vero Cells; Virus Replication - drug effects; Viruses
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632020101200602

Two inhibitors of cellular inosine monophosphate dehydrogenase, mycophenolic acid (MPA) and ribavirin, were evaluated for inhibitory activity against orthopoxviruses. Unrelated antipoxvirus agents tested for comparison included 6-azauridine, cidofovir (HPMPC) and cyclic HPMPC. MPA inhibited camelpox, cowpox, monkeypox and vaccinia viruses by 50% in plaque reduction assays at 0.2–3 μM in African green monkey kidney (Vero 76) and mouse 3T3 cells. Ribavirin was considerably more active in 3T3 cells (50% inhibition at 2-l2 μM) than in Vero 76 cells (inhibitory at 30–250 μM) against these viruses. In cytotoxicity assays, MPA and ribavirin were more toxic to replicating cells than to stationary cell monolayers, with greater toxicity seen in 3T3 than in Vero 76 cells. The superior antiviral potency and increased toxicity of ribavirin in 3T3 cells was related to greater accumulation of mono-, di- and triphosphate forms of the drug compared with Vero 76 cells. For both MPA and ribavirin, virus inhibition was closely correlated to the extent of suppression of intracellular guanosine triphosphate (GTP) pools. Treatment with extracellular guanosine (which restored intracellular GTP levels) did not lead to complete reversal of the anticowpox virus activity of ribavirin. This suggests that other modes of virus inhibition also appear to contribute to the anti-orthopoxvirus activity of ribavirin. Biological differences in mode of action and immunosuppressive potential between ribavirin and MPA may account for why the former compound is active against orthopoxvirus infections in animals and the latter inhibitor is not.