Inhibitory Effects ofAntiviral Compounds on Respiratory Syncytial VirusReplication InVitro

We examined theinhibitory effect of20antiviral compounds, including ribavirin, on thereplication of respiratory syncytial virus inHeLaandHEp-2cell cultures. Ofthecompounds studied, pyrazofurin and 3-deazaguanine emerged asmore potent inhibitors ofrespiratory syncytial virus thanribavirin. Basedon their inhibitory effect on thecytopathogenicity ofrespiratory syncytial virus inHeLacells, theaverage50%effective doseofpyrazofurin and3-deazaguanine foreight strains was 0.07and1.65,ug/ml, respectively; thatof ribavirin was 5.82p.g/ml. Thecytotoxicity ofthese compounds forHeLacells was examined bymonitoring the incorporation ofradiolabeled uridine intocellular RNA.Theselectivity indexes ofpyrazofurin and3deazaguanine exceeded thatofribavirin by70-and11-fold, respectively. Pyrazofurin, 3-deazaguanine, and ribavirin inhibited bothviral antigen expression andsyncytium formation inHeLacell cultures, asassessed by an indirect immunofluorescence assay.Inthese assays,pyrazofurin and3-deazaguanine againproved more potent thanribavirin. 2,5-Diamidinoindole andcarbodine were lesspotentthanribavirin. Variousother compounds, i.e., 3-adenin-9-yl-2-hydroxypropanoic acidisobutyl ester, 3-deazauridine, 3'-C-methyluridine, 5'-deoxy-5-fluorouridine, 5-cyanoimidazole-4-carboxamide, anditsribofuranosyl derivative, didnotinhibit the cytopathic effect oftheLongstrain ofrespiratory syncytial virus atconcentrations -125pLg/ml. Tubercidin, 5-chlorotubercidin, xylotubercidin, neplanocin A,thiosemicarbazone R,and3-methylquercetine were tootoxic toHeLacells fortheir inhibitory effects on respiratory syncytial virus tobeexamined. Respiratory syncytial virus (RSV)causes lowerrespiratorytractinfections suchasbronchiolitis andpneumonia in infancy andearly childhood. Mostclinicians consider RSV one ofthemostimportant agentsofacuterespiratory disease inchildren, andalmost 50%ofinfants areexpected tosuffer fromRSV infection during their first winter (15,16,20,32, 35). Inactivated RSV vaccine doesnotprotect against naturalinfection andleads toan unusual immuneresponseand even lunginflammation during thecourse ofa subsequent natural infection (21). Recent research efforts havetherefore focused on thedevelopment ofeither potentliveRSV vaccines oreffective antiviral compounds. Following reports that ribavirin may reduce theseverity of illness andamountofvirus shedinacuterespiratory infections duetoRSV or influenza B virus (13,14,23,37),the drughasbeenapproved inaerosol formforthechemotherapy ofRSV infections. Thishasprompted thesearch for antiviral compounds that may beas effective, ifnotmore effective, against RSVthanribavirin. We havenow investigatedtheinhibitory effects of20antiviral compounds, including ribavirin, on thereplication ofRSVinvitro.