Preclinical Development of HIV Vif Antagonists

SUMMARYThis revised application is for a Phase I SBIR grant under PAin which NIAID and DAIDS have expressed a special emphasis on thedevelopment of anti HIV agents directed at new viral or cellular targets for treatment of HIV infectionThe goal of our proposal is to address the call to evaluate novel drug targets by conducting preclinical studies for a first inclass antiretroviralARVtherapeutic for which we have obtained a strong foundation for mechanism of actionMOAthrough lead development of an HIVHIVVif antagonistThe compounds described herein enable the host cell factors APOBEC GA Gand APOBEC FA Finvolved in innate immunity to broadly neutralize HIV through APOBEC dependent hypermutation of viral genomes during reverse transcriptionWe have conducted medicinal chemistry to optimize leads with increased efficacy in the single digit nanomolar range against HIV isolates from clades AB and CSince the initial submission of this proposal we also have comprised a prodrug strategy to increase plasma half life in vivo and chemical synthesis for both the leadSNL and prodrugIrino Lhave been optimizedMoreoverADMET studies revealed promising parameters and have addressed the initial reviewersconcerns of toxicityBased on reviewer recommendations this SBIR proposal now seeks to prioritize detailed pharmacokineticPKstudieshumanized mice in vivo efficacy studiesand viral resistance studiesAs requested by the reviewersstudies required by the FDA under theGuidance for Industry Antiviral Product DevelopmentConducting and Submitting Virology Studies to the Agencyhave been moved to Phase II PROJECT NARRATIVE The revised SBIR Phase I proposal addresses the RFA call for novel drugs on novel viral targets that will address HIV drug resistance and the potential for a cureAPOBEC GA Gis an antiviral protein found in human white blood cells that inhibits viral replication by inducing mutations in the HIV viral genome and causing it to fail during replicationHoweveras its own defenseHIV expresses the Vif protein that binds to A G and thereby triggers its elimination by the host s intracellular protein digestion machineryDespite significant academic researchthere is an unmet need to identify small molecular antagonists of Vif with a validated mechanism of action that have clinical potentialWe have identified a highly potent Vif antagonist as a broadly neutralizing antiviral lead candidate for preclinical development that has been validated by third partiesThe proposed Phase I studies will produce preclinical and IND enabling data essential for regulatory approval and clinical trials for a first in class therapeutic and an opportunity to explore its curative potential