Substituted alpha-Hydroxy Acids and Their Thioesters as Pharmacophores: Development of New Peptide Derived Caspase Inhibitors

作为药效团的取代 α-羟基酸及其硫酯：新型肽衍生的 Caspase 抑制剂的开发

• 批准号: 5295082
• 负责人: Dr. Rolf Roers
• 金额: --
• 依托单位国家: 德国
• 项目类别: Emmy Noether International Fellowships
• 财政年份: 2000
• 资助国家: 德国
• 起止时间: 1999-12-31 至 2001-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5295082?language=en
• 关键词: Substituted; alpha; Hydroxy; Acids; Their

Caspases regulate cellular processes of fundamental importance to higher organisms, e.g. the promotion of inflammation of the mediation of apoptosis. While serving important homeostatic functions under normal conditions, the deregulation of inflammation and apoptosis can lead to fatal consequences. Therefore, pharmacological regulation or disruption of caspase mediated signalling pathways represents a promising therapeutic target which, in principle, can be achieved by using small molecule inhibitors. Peptidylic inhibitors of caspases have two components: the relevant pharmacophore moiety responsible for the inhibition of the enzyme, and a peptide element required for additional interactions near the active site.We reasoned that a combination of effective pharmacophore moieties with "morphed" peptide segments may be the key to synthesis of bioavailable strong inhibitors. We chose highly substituted a-hydroxy-ß-amino acids and their thioesters as general pharmacophoric moities and hydroxyethylene units as the "morphed" peptide segments. Semirational, combinatorial approach leading to the potential inhibitors should be possible by recent developments in asymmetric aldol reactions.

半胱氨酸天冬氨酸氨基转移酶调节对高等生物体至关重要的细胞过程，例如促进炎症和介导细胞凋亡。在正常情况下发挥重要的体内平衡功能的同时，放松对炎症和细胞凋亡的调控可能会导致致命的后果。因此，药物调节或破坏caspase介导的信号通路是一个有希望的治疗目标，原则上可以通过使用小分子抑制剂来实现。半胱氨酸天冬氨酸酶的多肽抑制剂有两个组成部分：负责抑制酶的相关药效团部分，以及活性部位附近额外相互作用所需的多肽成分。我们推测，有效的药效团部分与“变形”的多肽片段相结合可能是合成生物可用强抑制剂的关键。我们选择了高度取代的a-羟基-？-氨基酸及其硫代酯作为一般的药效基团，并选择了羟基乙烯单元作为“变形”的多肽片段。通过不对称Aldol反应的最新进展，半分子、组合方法得到潜在的抑制剂应该是可能的。