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HIV蛋白酶抑制剂的安全性和有效性摘要艾滋病流行是一场全球危机，全球有3100万人感染HIV。根据世界卫生组织2010年修订的抗逆转录病毒治疗指南，创造毒性较小的疗法是减少不良反应和提高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）的支柱，年销售额超过25亿美元。所有市售的HIV蛋白酶抑制剂（PI）都是细胞色素P450的底物，并与利托那韦（一种药代动力学加强剂）共同给药。加强维持化合物的治疗水平以抑制病毒复制并避免病毒突变的发生。利托那韦是细胞色素P4503 A4亚型的强效抑制剂，Ki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要。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、高血糖症和脂肪代谢障碍。消除PI的P450相互作用是几家制药公司的高优先级研究重点，包括Merck，Sequoia Pharmaceuticals和Concert Pharmaceuticals。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，并将增加治疗方案的依从性。本提案的具体目标是：目标1。设计并合成与FKBP配体连接的PI片段的新文库。目标2.采用酶促测定筛选和选择库化合物抑制HIV蛋白酶的能力，并评价体外pk/pd。目标3。重新筛选目标2产生的最佳PI候选物的微粒体稳定性、细胞感染性试验中的效价和p-糖蛋白试验，以选择候选物进行进一步的临床前评价。 公共卫生相关性：与HAART依从性患者相比，不依从HAART的HIV患者每患者年的死亡风险至少增加7倍。最近的一项数据荟萃分析显示，北美的依从率仅为55%。HAART相关毒性是不依从性的主要原因，多达37%的患者在两年内因不良事件而需要调整治疗。通过降低HIV蛋白酶抑制剂的毒性，我们希望改善HAART的依从性和治疗结果。

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.