Developing Multi-targeting Antiviral Agents Against Herpes Simplex 1

Viruses from the human herpesvirus family are estimated to infectof the adult population worldwide and are responsible for lifelong debilitating and congenital infectionsSome members of this family are associated with human cancers and age related cognitive declineHerpes simplex virusHSVhas infected more thanbillion people under the age ofof the populationHSVcauses significant disease during acute infectionoral and genital lesionscorneal blindness and encephalitisand establishes persistent latent infections in sensory neurons for the life of the host with the potential for reactivation and recurrent diseaseIn the USthe economic burden of HSV infection due to social and medical concerns is estimated at over $million each yearOther members of the herpesvirus family are associated with even more severe disease states especially in immunocompromised individualsAlthough much of the impact of herpesvirus pathogenesis can be controlled by drug therapythe emergence of drug resistance has threatened these treatment effortsWe have formed a new start up ventureQuercus Molecular DesignQMD LLCwhose long term objective is to identifycharacterizeand exploit multiple drug targets of human herpesvirusesQMD will leverage decades of HSV genetic and biochemical research from DrSandra Weller s laboratory with DrDennis Wright s expertise in small molecule drug discovery and development in infectious diseaseExisting strategies for development of new herpesvirus therapies have focused on individual viral targets such as the viral polymeraseQMD is focused on developing novel therapeutic agents for HSV by pursuing multi targeting inhibitors that block two or more essential viral proteins that fall into the nucleotidyltransferase superfamilyNTSThis approach is expected to lead to the production of antivirals that are less susceptible to the development of mutation based resistanceHSV encodes three essential NTS proteins that are characterized by the presence of an acidic catalytic triadviral single strand DNA binding proteinICPviral terminaseULand viral alkaline nucleaseULSmall molecule inhibitors that bind at this site are hypothesized to exhibit potent inhibition of at least two of the proteinsthereby drastically limiting the onset of resistanceIn Aimwe will prepare lead likedual metal directed chemotypes as multi target inhibitors of HSV proteinsIn Aimwe will test lead compounds for efficacy in biochemical assays for ICPULand ULactivity and for reduction of virus productionWe anticipate the identification of multiple lead scaffolds that target two or more of the enumerated viral targets and exhibit antiviral activityUpon completion of the work in this phase I applicationwe will be well positioned to pursue further development of novel antiviral agents for treatment of HSV infections