Designing HIV Protease Inhibitors with Lower Dosing Requirements and Lower Toxici

摘要艾滋病的流行是一个全球性的危机，全世界有3100万人感染了艾滋病毒。根据世界卫生组织2010年对抗逆转录病毒治疗指南的修订，创造毒性较小的治疗方法是减少不良影响和提高治疗方案依从性的首要任务。HIV蛋白酶抑制剂是高活性抗逆转录病毒疗法（HAART）的主要药物，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，并与利托那韦（一种药代动力学增强剂）共同给药。增强维持治疗水平的化合物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，具有Ki 5-70 nM，有助于减少共给药PI的P450相互作用。消除PI的P450相互作用也会消除对利托那韦的需求。利托那韦单独使用或与其他HIV蛋白酶抑制剂（PI）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相互作用是包括默克、红杉制药和Concert制药在内的几家制药公司的高度优先研究重点。短期研究显示，停用利托那韦可减少与HAART相关的毒性，并可提高治疗方案的依从性。本建议的具体目标是：目标1。设计和合成一个新的与FKBP配体连接的PI片段库。目标2。筛选和选择文库化合物抑制HIV蛋白酶的能力，采用酶分析和评估体外pk/pd。目标3。重新筛选Aim 2中产生的最佳PI候选物，进行微粒体稳定性、细胞感染性检测效力和p-糖蛋白检测，以选择候选物进行进一步的临床前评估。

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. PUBLIC HEALTH RELEVANCE: HIV patients who fail to comply with HAART have at least a 7-fold increased risk of mortality per patient year compared with HAART adherent patients. A recent meta-analysis of data showed adherence rates of only 55% in North America. HAART-associated toxicities are a major cause of non-adherence with as many as 37% of patient requiring modifications to their treatment due to adverse events over a two year period. By reducing the toxicity of HIV protease inhibitors, we hope to improve compliance with HAART and therapeutic outcomes.