Developing a novel antifungal targeting Gwt1 for the treatment of invasive aspergillosis and rare mold infections

ABSTRACTInvasive fungal infections are a leading cause of death in patients with compromised immune systemsWith amortality rateinvasive aspergillosisdue primarily to Aspergillus fumigatussurpasses invasive candidiasis as the most frequent fungal cause of deathFollowing IAthe greatest fungal killers are other invasive mold infectionse gFusariumScedosporiumand mucormycosisSuccessful treatment of these invasive mold infections is notoriously difficult due to inadequate clinical efficacy of current drugslack of activity against increasingly resistant strainsantifungal toxicitydrug interactionsand requirements of drug monitoringInnovative agents that exploit novel targets and are active against resistant strains are critically neededOur unique effort to identify novel therapeutics to treat IA has focused on targeting the fungal protein GwtsynthaseThe Gwtenzyme is part of a multistep process required for the assembly of glycosylphosphatidylinositolGPIanchored mannoproteins that form the outermost component of the critically important fungal cell wallThis antifungal target is important due tothe paramount role of Gwtin maintaining fungal cell wall integritylow homologyltamino acid sequence identitywith the closest mammalian orthologPIG Wenabling selective inhibition of Gwtandthe potential to avoid cross resistance with existing antifungals due to the completely new mechanism of actionAmplyx Pharmaceuticals is currently in Phaseclinical trials with APXthe first in class prodrug of the Gwtinhibitor APXAWe will leverage our extensive structure activity relationship expertise to create new Gwtinhibitors with greater antifungal activity against Aspergillus sppas well as other rare invasive mold infections with the goal of identifying a differentiated back up compound to combat the significant mortality associated with these invasive fungal infectionsAimSynthesize a compound libraryGwtanalogs in an iterative synthesis screening processAimCharacterize and select compounds for advancement through extensive in vitro studiesWe will assessaantifungal activity against Afumigatus and rare moldsbtarget engagementccytotoxicitydexpanded antifungal activity against resistant strainsecell permeabilityCacocellsfmicrosomal stabilitygformulation testinghhERG interactionandicytochrome Pisoform interactionAimAssess up tolead compounds in murine dosingIA and mucormycosis efficacy studiesand advanced microbiology assaysWe will defineapharmacokineticsPKbmaximum tolerated doseMTDcreduction in fungal burdendsurvivaletime killandfdevelopment of resistanceImpactSuccessful completion will trigger IND enabling studies of a novelbroad spectrum Gwtantifungal agentwhich is acutely needed for empiric treatment in high risk patientsgiven the complexity of accurate early diagnosis of invasive fungal infections