Irreversible inhibitors of cholesterol esterase

胆固醇酯酶不可逆抑制剂

• 批准号: 6413125
• 负责人: LORRAINE Marie DECK
• 金额: $ 13.75万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2005-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6413125
• 关键词: chemical models; chemical structure function; cholesterol; drug design /synthesis /production; enzyme activity; esterase inhibitor; gastrointestinal nutrient absorption; nutrition related tag; pyrones; serine proteinases; sterol esterase

Pancreatic cholesterol esterase (CE) has a dual function in the absorption of dietary cholesterol. First, CE catalyzes the hydrolysis of cholesterol esters to liberate cholesterol for absorption; second, CE transports cholesterol from micelles to the surface of the enterocyte where absorption takes place. There is also evidence that CE functions within the enterocyte to re-esterify cholesterol in the pathway leading to the formation of chylomicrons. It is our hypothesis that inhibition of any of these functions of CE would provide a new approach to the treatment of hypercholesterolemia through limiting the bioavailability of dietary cholesterol. This proposal will focus on the development of irreversible inhibitors of CE for prevention of the hydrolysis of cholesterol ester. CE is a serine esterase with a catalytic mechanism that is similar to that of serine proteases. We propose to develop selective irreversible inhibitors of CE. Our specific aims are: (1) to develop versatile schemes for the synthesis of haloenol lactones such as substituted 6-chloropyrones as potential irreversible inhibitors of cholesterol esterase, and (2) to use molecular modeling and kinetic studies to reduce structure-activity relationships for the development of selective inhibitors of CE. Our preliminary work demonstrates the versatility of the synthetic schemes that we have developed. Selectivity will be determined at the enzyme level by screening compounds for their rates of inactivation of CE compared with the proteases chymotrypsin, trypsin and elastase, all of which are serine proteases that function within the intestine.

胰腺胆固醇酯酶（CE）在吸收膳食胆固醇方面具有双重功能。首先，CE催化胆固醇酯水解，释放胆固醇供吸收；其次，CE 将胆固醇从胶束转运至发生吸收的肠上皮细胞表面。还有证据表明，CE 在肠上皮细胞内发挥作用，在导致乳糜微粒形成的途径中重新酯化胆固醇。我们的假设是，抑制 CE 的任何这些功能将通过限制膳食胆固醇的生物利用度来提供治疗高胆固醇血症的新方法。该提案将重点开发 CE 的不可逆抑制剂，以防止胆固醇酯的水解。 CE是一种丝氨酸酯酶，其催化机制与丝氨酸蛋白酶相似。我们建议开发CE的选择性不可逆抑制剂。我们的具体目标是：(1) 开发合成卤烯醇内酯的通用方案，例如取代的 6-氯吡喃酮作为胆固醇酯酶的潜在不可逆抑制剂，以及 (2) 利用分子模型和动力学研究来减少构效关系，以开发选择性 CE 抑制剂。我们的初步工作证明了我们开发的合成方案的多功能性。通过筛选化合物与胰凝乳蛋白酶、胰蛋白酶和弹性蛋白酶（所有这些都是在肠道内起作用的丝氨酸蛋白酶）相比的CE失活率，在酶水平上确定选择性。