InVitro Antiviral Activity ofMycophenolic Acid andItsReversal byGuanine-Type Compounds

>Withtheagardiffusion testandBS-C-1cells, mycophenolic acid was foundto give a straight-line dose-response activity ininhibiting thecytopathic effects of vaccinia, herpes simplex, andmeasles viruses. Plaque tests haveshown100%reduction ofvirus plaques bymycophenolic acid overdrug rangesof10to50Ag/ml and virus input ashigh as6,000 plaque-forming units (PFU)perflask. Backtitration studies withmeasles virus inhibited bymycophenolic acidhaveindicated that extracellular virus titers were reduced byapproximately 3logs1o andtotal virus was reduced by1logl0. Theagardiffusion testsystemlends itself readily todrugreversal studies. Mycophenolic acidincorporated into agarat10,g/ml gave100% protection tovirus-infected cells. Filter paperdiscs impregnated withselected chemical agents atconcentrations of1,000 ,ug/ml (20Agperfilter paperdisc) were placed on theagarsurface. Reversal oftheantiviral activity ofmycophenolic acid was indicated byvirus breakthrough inthose cells inclose proximity tothefilter paperdisc. Chemicals showing thebestreversal oftheantiviral activity ofmycophenolic acid wereguanine, guanosine, guanylic acid, deoxyguanylic acid, and2,6diaminopurine. Thereversal ofantiviral activity was confirmed bytitrations of virus produced withvarious amountsofbothmycophenolic acidandguanine present andbyisotope tracer methods withuptakes oflabeled uridine, guanine, leucine, andthymidine intreated andnontreated, infected andnoninfected cells as parameters. Allantiviral effects ofmycophenolic acidat10,ug/ml couldbereversed totherangeshownbyuntreated controls bytheaddition of10,ug/ml of those chemicals exhibiting reversal activity.