Research Project
10395011
Since the introduction of combination antiretroviral therapy (cART) the survival and quality of life of people living with HIV (PLWH) in the Western world has continued to improve. However, HIV infection and cART are associated with glucose and lipid metabolism dysregulation, obesity, an increased prevalence of metabolic syndrome, and a higher incidence of cardiovascular disease. In fact, cardiovascular disease is becoming a leading cause of morbidity and mortality in the PLWH patient population. The metabolic side effects are variably associated with the use of most current key cART therapeutics (e.g., the widely used fixed- dose combinations Atripla and Kaletra, and the new integrase inhibitors and protease inhibitors), although they are generally less troublesome than such effects from earlier antiretrovirals. Here, we propose an innovative approach to identify small molecules to modulate and normalize metabolic control by targeting a pathway dysregulated in HIV and chronic inflammation. To this end, we will carry out a high-throughput screening campaign in a 1536-well plate format in conjunction with a tiered approach to screen the >665,000-compound Scripps Drug Discovery Library (SDDL) and confirm the potency of ~500 drug-like molecules. 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 both the existing compound libraries and other commercial sources. Hit scaffolds will be triaged to remove intractable molecules. We will select 3-5 molecular series from the most promising hits, which will be profiled to verify their selectivity, potency, and lack of cytotoxicity. Using an orchestrated effort from the applicant laboratories (Scripps California and Scripps Florida), 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 and can be evaluated for appropriate phenotypic responses to cell-expression levels. This will be followed by in vitro and 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 testing in rodent efficacy models such as HIV transgenic rats. 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.
