Novel Aglains as Therapeutic Agents for Mosquito-borne Arboviruses

PROJECT SUMMARY/ABSTRACT Novel Aglains as Therapeutic Agents for Mosquito-borne Arboviruses This proposed R01 research program seeks to develop novel aglain derivatives as host-targeted antivirals against dengue virus (DENV) and other mosquito-borne arboviruses. DENV ranks among the World Health Organization's top ten threats to public health worldwide and is listed as an NIH Category A Priority Pathogen. Current treatment options for DENV are limited and include an approved vaccine with modest efficacy. Moreover, there is a severe lack of approved DENV antiviral agents and an urgent need for therapeutics that can reduce morbidities and lower infection burden. We have identified aglains such as CMLD013854 with potent activity against DENV-2 which extends to all other DENV serotypes. In early structure-activity relationship (SAR) studies, we have begun to map the structural requirements necessary for efficacious antiviral activity, including enantiospecificity. Target identification experiments, including the Proteome Integral Stability Alteration (PISA) assay, have identified the host target vesicle amine transport 1 (VAT-1), a member of the NADPH-dependent quinone oxidoreductase family, as the host target modulating antiviral aglain action. Here, we seek to optimize the aglain chemical series as a new class of host-targeted antivirals. Further, we will use CMLD013854 and other antiviral aglains as tool compounds to study their modulation of VAT-1 and define the antiviral consequences of VAT-1 inhibition to DENV infections. Our medicinal chemistry program will map antiviral aglain SAR by systematically varying four regions of the aglain core and use this SAR to guide optimization of potency, selectivity, and pharmacological properties. Our lead optimization efforts will focus primarily on DENV, but will also extend to other mosquito-borne viruses including CHIKV and ZIKV, both listed as NIH Category B Priority Pathogens. To guide the project, we will deploy focused advancement criteria to ensure prioritization of leads with optimal activity and pharmacological profiles. Other key objectives of this project include biochemical assays to interrogate CMLD013854's mode- of-action targeting VAT-1, X-ray crystallography of VAT-1/aglain co-complexes, studies to define the role of VAT-1 in DENV-2 infection, and execution of pharmacokinetic, safety, and in vivo antiviral efficacy studies for top aglains, including murine infection models for both DENV and ZIKV. This multidisciplinary collaboration will be jointly led by PIs with complementary expertise in organic synthesis/target identification (Porco) and virology (Chu) and is enhanced by co-Investigators with expertise in medicinal chemistry (Brown) and structural biology/biochemistry (Allen). Successful execution of this project will advance a novel class of antivirals and build a comprehensive understanding of their unique mode-of-action.