An Innovative Approach to Identify Correctors of Metabolic Complications in HIV

自从引入抗逆转录病毒联合治疗（cART）以来，西方世界艾滋病毒感染者（PLWH）的生存和生活质量持续改善。然而，HIV感染和cART与糖脂代谢失调、肥胖、代谢综合征患病率增加和心血管疾病发病率升高有关。事实上，心血管疾病正在成为PLWH患者发病率和死亡率的主要原因。代谢副作用与目前大多数关键cART疗法的使用有不同的关系（例如，广泛使用的固定剂量组合Atripla和Kaletra，以及新的整合酶抑制剂和蛋白酶抑制剂），尽管它们通常比早期抗逆转录病毒药物的副作用更麻烦。在这里，我们提出了一种创新的方法，通过靶向HIV和慢性炎症中失调的途径来识别调节和正常化代谢控制的小分子。为此，我们将以1536孔板形式开展高通量筛选活动，并结合分层方法筛选bbb665,000个化合物Scripps Drug Discovery Library (SDDL)，并确认约500个药物样分子的效价。将使用平行和正交试验以及使用多重反筛进行脱靶评估，进行命中验证以识别小分子调节剂并消除非特异性效应物。为了优先考虑hit scaffold系列，我们将从现有化合物库和其他商业来源中选择已确认的hit的类似物。被击中的支架将被分类去除难处理的分子。我们将从最有希望的hit中选择3-5个分子系列，对其进行分析，以验证其选择性，效力和缺乏细胞毒性。在申请人实验室（Scripps California和Scripps Florida）的精心策划下，将制定2-4系列的先导物，并重新测试其效力/选择性，目的是推进先导物，使其能够在上述试验中引起适当的体外反应，并可以评估细胞表达水平的适当表型反应。随后将进行体外和体内药代动力学（PK）研究，以确定1-2个顶级支架供进一步研究。最后，将选择最有前途的2-3种具有良好药物代谢和药代动力学（DMPK）特性（包括高口服生物利用度）的化合物，在啮齿类动物模型（如HIV转基因大鼠）中进行体内试验。总之，我们提出了一种新的策略来建立新的和更有效的治疗方法来改善HIV相关的代谢并发症，这是一个重要的未满足的临床需求，也是NIDDK使命中高度优先的HIV/AIDS研究领域。

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.