Designing HIV Protease Inhibitors with Lower Dosing Requirements and Lower Toxici

描述(由申请人提供)：通过细胞内靶向优化艾滋病毒蛋白酶抑制剂的安全性和有效性摘要艾滋病流行是一种全球危机，全世界有3100万艾滋病毒携带者。根据世界卫生组织2010年修订的抗逆转录病毒治疗指南，创造毒性较低的疗法是减少不良反应和改善治疗方案依从性的首要任务。HIV蛋白酶抑制剂是高效抗逆转录病毒疗法(HAART)的中流砥柱，年销售额超过25亿美元。所有上市的HIV蛋白酶抑制剂(PI‘s)都是细胞色素P450的底物，并与药代动力学增强剂利托那韦联合使用。增强维持化合物的治疗水平，以抑制病毒复制和避免病毒突变的发生。利托那韦是细胞色素P4503A4异构体的强抑制剂，其Ki值为5-70 nM，有助于减少联合给药PI的P450相互作用。消除PI的P450相互作用也将消除对利托那韦的需求。利托那韦单独或与其他HIV蛋白酶抑制剂(PI‘s)联合使用的毒性包括肝毒性、颈动脉增厚、高胆固醇血症、高血糖和脂肪营养不良。消除PI的P450相互作用是几家制药公司高度优先的研究重点，包括默克公司、红杉制药公司和Concert制药公司。在短期研究中，利托那韦的消除已被证明可以减少与HAART相关的毒性，并将增加对治疗方案的依从性。本建议的具体目的是：目的1.设计和合成一个与FKBP配体相连的PI片段文库。目的2.用酶法筛选抑制HIV蛋白水解酶活性的文库化合物，并在体外评价PK/PD。目的3.从微粒体稳定性、细胞感染性测定和P-糖蛋白测定中重新筛选目标2所产生的最佳PI候选者，以选择用于进一步的临床前评价的候选者。

DESCRIPTION (provided by applicant): Optimizing HIV Protease Inhibitor Safety and Efficacy via Intracellular Targeting Abstract The AIDS epidemic is a global crisis with 31 million people worldwide who are living with HIV. According to the World Health Organization's 2010 revision of antiretroviral treatment therapy guidelines, creating less toxic therapies is a top priority to reduce adverse effects and improve compliance with therapeutic regimen. HIV protease inhibitors are a mainstay of highly active antiretroviral therapy (HAART) with annual sales of over $2.5 billion. All marketed HIV protease inhibitors (PI's) are substrates for cytochrome P450 and are co- administered with ritonavir, a pharmacokinetic booster. Boosting maintains therapeutic levels of compound to suppress viral replication and avoid incidence of viral mutation. Ritonavir is a strong inhibitor of the cytochrome P4503A4 isoform with a of Ki 5-70 nM which helps reduce P450 interactions of the co- administered PI. Eliminating P450 interactions of PI's would also eliminate the need for ritonavir. Toxicities attributed to ritonavir used alone or in combination with other HIV protease inhibitors (PI's) include hepatotoxicity, carotid artery thickening, hypercholesterolemia, hyperglycemia, and lipodystrophy. The elimination of P450 interactions for PI's is a high-priority research focus at several pharmaceutical companies, including Merck, Sequoia Pharmaceuticals, and Concert Pharmaceuticals. The elimination of ritonavir has been shown to reduce toxicities associated with HAART in short-term studies, and would increase compliance with therapeutic regimens. The specific aims of this proposal are: Aim 1. Design and synthesize a novel library of PI fragments linked to FKBP ligands. Aim 2. Screen and select library compounds for the ability to inhibit HIV protease employing an enzymatic assay and evaluate in vitro pk/pd. Aim 3. Re-screen the best PI candidates resulting from Aim 2 for microsomal stability, potency in cell infectivity assays, and p-glycoprotein assays to select candidates for further preclinical evaluation.