TOWARD PEPTIDEMIMETIC INHIBITORS OF ASPARTIC PROTEASES

天冬氨酸蛋白酶的拟肽抑制剂

• 批准号: 2519001
• 负责人: DANIEL H RICH
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519001
• 关键词: X ray crystallography; aspartic endopeptidases; chemical binding; chemical models; drug design /synthesis /production; pepsin; peptide analog; protease inhibitor

This is a synthetic, structure-based drug design proposal directed toward finding novel peptidemimetics that inhibit aspartic and other proteases. Peptidemimetics are low molecular weight non-peptide molecules that bind to the target enzyme or receptor in a fashion close to that of the natural peptide ligand. Since many putative peptidemimetics are structurally related to classical, heterocyclic drugs that are well absorbed, true peptidemimetics are expected to possess desirable pharmacodynamic properties superior to the natural peptides due to their improved oral activity and duration of action. The potential benefits to clinical medicine are enormous if this goal can be achieved. Several non-peptide inhibitors of pepsin, penicillopepsin and other aspartic proteases will be designed, synthesized, and evaluated as part of a long term, collaborative effort to find ways to obtain non-peptide (or minimally peptide) inhibitors of proteases. Compounds will be designed in collaboration with Dr. Regine Bohacek, CIBA, by use of GrowMol, Dr. Bohacek's computerized structure-generating program that generates novel structures in the active site of a target enzyme atom-by- atom. Selected analogs will be synthesized and assayed in my laboratory for potency against the target enzyme. The X-ray crystal structure will be obtained for pepsin-inhibitor complexes and penicillopepsin-inhibitor complexes when suitable inhibitors are identified; this work will be done in collaboration with Dr. Hazel Holden, Associate Professor at UW- Madison. We have chosen the aspartic protease pepsin to carry out the initial studies because of the large body of structure-activity data that will help guide our selection of early synthetic targets, because of my extensive experience synthesizing inhibitors of this system, and because of the importance of several aspartic proteases, including HIV protease, renin and cathepsin D, as potential therapeutic targets. Critical to the successful evaluation of structure based drug design using GrowMol is our ability to determine the actual mode of binding by X-ray crystallography so as to evaluate how well the computer-generated predictions work.

这是一个基于合成的，基于结构的药物设计建议 找到抑制天冬氨酸和其他蛋白酶的新型肽仪。 肽光学是低分子量的非肽分子的低分子量 以接近靶标的酶或受体 天然肽配体。 由于许多假定的肽仪是 与经典的杂环药物结构相关的结构相关 被吸收的，真正的肽仪有望拥有可取的 由于它们 改善了口腔活动和作用持续时间。 潜在的好处 如果可以实现此目标，那么临床医学是巨大的。 胃蛋白酶，青霉素和其他几种非肽抑制剂 天冬氨酸将被设计，合成和评估为一部分 长期的协作努力，以寻找获得非肽的方法 （或最小肽）蛋白酶的抑制剂。 化合物将是 与CIBA的Regine Bohacek博士合作设计 Growmol，Bohacek博士的计算机结构生成计划 在靶酶原子的活性位点生成新结构 原子。 选定的类似物将在我的实验室中合成和测定 抗靶酶的效力。 X射线晶体结构将 可以获得胃蛋白酶抑制剂复合物和青霉素抑制剂 当鉴定出合适的抑制剂时，复合物；这项工作将完成 与UW-副教授Hazel Holden博士合作 麦迪逊。 我们选择了天冬氨酸蛋白酶胃蛋白酶进行 初步研究是因为大量的结构活性数据 由于我的 丰富的经验综合了该系统的抑制剂，因为 几种天冬氨酸的重要性，包括HIV蛋白酶， 肾素和组织蛋白酶D作为潜在的治疗靶标。 对 成功评估基于结构的药物设计使用growmol是我们的 通过X射线晶体学确定实际结合模式的能力 以评估计算机生成的预测的效果。