Novel Small Molecule Therapeutics Inhibiting Zika Virus Infection

Abstract Zika virusZIKVa flavivirusis the cause of the recent pandemic of infections across both North and South America often associated with serious neurological damageincluding congenital microcephaly in newborns and Guillain Barrsyndrome in adultsAccording to the CDCalmostof women who were infected with ZIKV during pregnancy give birth to babies with severe birth defectsincluding microcephaly and brain abnormalitiesLong term damage caused by ZIKV infection to newborns of women who were infected with ZIKV during pregnancy is still unclearDespite the significant medical need for prophylactic or therapeutic treatmentsno vaccines or drugs have been approved for ZIKV infectionsThe overall goal of this project is to address this significant unmet medical need by developing novel scaffolds of small molecule inhibitors of ZIKV for prophylactic and therapeutic useThe strategy of this proposal is to optimize the potencyselectivity and drug like properties of a novel phenylcarbamoylPCAseries of compounds that we previously demonstrated to inhibit ZIKV infections in culture and to develop resulting prioritized analogs into anti ZIKV drugsPCA analogs exhibit ICvaluesM vs ZIKV in cultureare tolerated at doses up to a solubility limited dose ofmg kg in mice via IP administrationand exhibit murine plasma availability andgtfold above the ICfor up tohrsThe chemical optimization of this proposal is designed to maximize the potencyselectivityand dug like properties to generate in vivo validated lead compounds with efficacy against AsianAfricanand South American strains of ZIKVThe approach is to leverage our experience in chemical synthesis and in cell based infectionviral entry and viral replication assays to optimize this PCA scaffoldIn Phase I of this projectin AimSAR based chemical optimization will be applied to maximize the anti ZIKV potency and selectivity of the PCA inhibitor seriesIn Aimthe activity of analogs will be evaluated versus infectious ZIKV strains isolated from UgandaSouth Asiaand South Americaand prioritized based on their activityselectivityand solubilityThe mechanism of action of resulting prioritized compounds will be investigated in a variety of cellular assays for ZIKV and other RNA viruses to determine the antiviral spectrum and verify selective antiviral activityIn Aimanalogs will be prioritized by their in vitro ADME propertiesformulations for IP administration will be developedand in vivo tolerability and PK profiles of PCA analogs with high potency and selectivity will be determinedIn Aimprioritized PCA analogs with favorable in vitro ADME properties and in vivo PK profiles will be evaluated for efficacy against ZIKV infection in a mouse model to define in vivo validated leadsIn Phase IIlead compounds will be optimized further to improve pharmacokinetic properties as well as efficacy and selectivity to generate a preclinical candidate and a backup compound Narrative The World Health Organization has declared Zika viruswhich has been associated with microcephaly in newborns and Guillain Barrsyndrome in adultsapublic health emergency of international concernTo address the lack of FDA approved vaccines and drugsthis proposal aims to develop novel compounds that inhibit ZIKV infection with favorable selectivity and to develop them into important drugs to treat ZIKV infections