Antiviral activities of mizoribine and other inosine monophosphate dehydrogenase inhibitors against several ortho- and paramyxoviruses

Abstract

Mizoribine (4-carbamoyl-1-β-D-ribofuranosylimidazolelium-5-olate), EICAR (5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), mycophenolic acid and ribavirin are antiviral agents targeted for inosine monophosphate (IMP) dehydrogenase. These compounds have been examined for their activities against orthomyxoviruses [influenza viruses (FluV)] and paramyxoviruses [parainfluenza viruses (PFluV), mumps virus, measles virus (MLSV) and respiratory syncytial virus (RSV)] in vitro. Mizoribine was 1- to 9-fold more active than ribavirin against RSV, PFluV and MLSV. EICAR and mycophenolic acid showed higher potency than mizoribine and ribavirin against all myxoviruses examined. None of the four compounds examined proved cytotoxic to stationary host cells (HeLa, Vero and MDCK) at a concentration of 200 μ9 ml-1 or more. On the other hand, EICAR and mycophenolic acid were toxic to rapidly growing cells at concentrations of 2.2-9 and 0.1-1.1 μg ml-1, respectively. Mizoribine and ribavirin showed cytotoxicity to the growing cells at higher concentrations (12-51 μg ml-1). The antiviral activities of mizoribine against FluV and RSV were reversed by 25-100 μM of each of guanosine and guanosine monophosphate (GMP). The antiviral activity of ribavirin against FIuV was reversed by 25 μg of each of guanosine and GMP, while its activity against RSV was reversed by ≥100 μM of each of these compounds. Neither xanthosine nor xanthosine monophosphate (XMP) reversed the antiviral effects of mizoribine and ribavirin at concentrations of 300 μM. Concentrations 9 times higher than the median effective doses (EC50) of mizoribine and ribavirin inhibited the growth of RSV in HeLa cells as determined in an assay of infectious virus yield. Mizoribin should be further pursued as a candidate drug for the treatment of ortho- and paramyxovirus infections.