Summary Since the introduction of combination antiretroviral therapy (ART) the survival and quality of life of people with HIV (PWH) in the Western world has continued to improve. However, HIV infection and ART are associated with metabolic dysregulations, dyslipidemia, obesity, and increased prevalence of metabolic syndrome. Cardiovascular disease is becoming a leading cause of morbidity and mortality in PWH. Here, we propose an innovative approach to identify and characterize highly selective chemical probes to a validated therapeutic target dysregulated in HIV and chronic inflammation that has so far proved difficult to modulate selectively. To this end, using an orchestrated effort from the applicant laboratories, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology (UF Scripps) in Jupiter, FL and Scripps Research in La Jolla, California, we will carry out a high-throughput screening (HTS) campaign in a 1536-well plate format in conjunction with a tiered approach to screen the ~666K UF Scripps Drug Discovery Library (UF- SDDL), which is enriched in compounds of drug likeness and chemical diversity, and the majority with high Central Nervous System Multiparameter Optimization (CNS MPO) scores. Hit-validation will be performed to identify small molecule regulators and eliminate nonspecific effectors, using parallel and orthogonal assays as well as off-target assessments using multiple counterscreens. To prioritize hit scaffold series, we will select analogs of confirmed hits from compound libraries and commercial sources. Hit scaffolds will be triaged to remove intractable molecules. We will select 3-5 scaffolds from the most promising hits, which will be profiled to verify their selectivity, potency, and lack of cytotoxicity. Leads in 2-4 series will be formulated and retested for potency/selectivity with the aim of advancing leads that can elicit the appropriate in vitro response in the aforementioned assays. This will be followed by in vivo pharmacokinetics (PK) studies to identify 1-2 top scaffolds for further investigation. Finally, the most promising 2-3 compounds with favorable drug metabolism and pharmacokinetics (DMPK) properties including high oral bioavailability, will be selected for in vivo efficacy testing. Altogether, we propose a novel strategy to establish new and more effective therapies to ameliorate HIV- associated metabolic complications, which is an important unmet clinical need and an area of high priority HIV/AIDS research within the mission of the NIDDK.

Narrative Metabolic and cardiovascular complications of HIV and antiretroviral therapy are leading causes of premature aging associated with long-term HIV disease. This proposal will use advanced strategies for high-throughput screening and subsequent chemical optimization to identify and characterize novel highly selective chemical probes to a validated therapeutic target that has so far proven challenging, despite strong rationale. Altogether, this proposal aims to address the significant unmet clinical need for new and more effective therapies to ameliorate HIV- and ART-associated metabolic complications.