Inhibitors of virus glycoprotein-LAMP1 receptor binding for Lassa virus therapy

Summary Since its discovery inLassa virusLASVa bi segmented RNA virus from the family Arenaviridaehas been recognized as the cause of disease affecting a quarter million people per yearresulting indeaths annually in West AfricaDue to global travelthere have been numerous confirmed cases of LASV infection outside West Africa including the USIts ability to spread as an aerosol and a case fatality rate ofmake LASV a major threat to human health and a BSLpathogenUnfortunatelyno FDA approved drugs or vaccines are available for treatment of LASVThe overall goal of this project is to address this medical need by identifying and validating small molecule inhibitors of LASV infection as prophylactics and or therapeuticsThe strategy of this project is to identify small molecule inhibitors that target the cellular entry of LASVBeing the first step in viral infection and occurring in the extracellular endosomal environmentviral entry is a susceptible and accessible target for antiviral therapyThe approach is to leverage our experience with a homogeneousbiochemicalhigh throughput screeningHTSmethodAlphaLISAto identify small molecules that prevent interactions between the glycoprotein of LASV and its host receptor LAMPPreviouslywe developed and applied a biochemical HTS based on AlphaLISA technology to identify compounds that block the Ebola glycoproteinGPbinding to its host receptor NPCTwo distinct scaffolds were identified and one exhibited potency against infectious Ebola virus in a murine in vivo studyIn Phase Ifor Aiman AlphaLISA HTS will be developed and optimized for the identification of small molecules that inhibit the interaction between LASV GPand its receptor LAMPIn Aima biolayer interferometryBLIbiochemical assay and cell based secondary assays utilizing recombinant vesicular stomatitis virusVSVcarrying arenavirus glcyoproteinsGPin place of VSV GP will be built and optimized to confirm initial hits from the primary screento determine which interacting partner they bindand to approximate the affinity of that interactionIn Aimthe HTS will be applied to diverse chemical librariesand hits will be confirmed in the secondary assaysIn Aimhits will be validated in infectious Lassa virus assays and prioritized by drug like structural features and in vitro ADME propertiesTogetherthese assays will identify and validate compounds that suppress LASV infection by inhibiting viral entry and will provide valuable information for prioritizing those inhibitorsIn Phase IIwe will chemically optimize priority inhibitors for potency and selectivity and evaluate them in animal infection models Narrative Lassa virusLASVa BSLpathogenis a global health concern with no FDA approved treatmentThis proposal aims to discover novel compounds that block infection of LASV by inhibiting the interaction between the virus glycoprotein and its entry receptor from host cellsSuch early acting inhibitors could be developed into important drugs to treat LASV infections