Screening‐based discovery of Aspergillus fumigatus plant‐type chitinase inhibitors

摘要

AlimitedtherapeuticarsenalagainstincreasingclinicaldiseaseduetoAspergillusspp.necessitatesurgentcharacterisationofnewantifungaltargets.Herewedescribethediscoveryofnovel,lowmicromolarchemicalinhibitorsofAspergillusfumigatusfamily18plant‐typechitinaseA1(AfChiA1)byhigh‐throughputscreening(HTS).AnalysisofthebindingmodebyX‐raycrystallographyconfirmedcompetitiveinhibitionandkineticstudiesrevealedtwocompoundswithselectivitytowardsfungalplant‐typechitinases.TheseinhibitorsprovidenewchemicaltoolstoprobetheeffectsofchitinaseinhibitiononA.fumigatusgrowthandvirulence,presentingattractivestartingpointsforthedevelopmentoffurtherpotentdrug‐likemolecules...