具有新型核心结构的肽类BACE1抑制剂的设计、合成及活性评价

以KMI-008为先导化合物，4-羟基或氨基取代的脯氨酸模拟其Pns，设计并合成了19条肽序列，用时间分辨荧光法测定目标肽体外对BACE1的抑制作用. 所合成化合物对BACE1有一定的抑制作用，其中两个化合物(LK-MX-41、LK-MX-42)与先导化合物活性相近，其核心结构由L-Phe-D-Pro组成，可以模拟BACE1的催化中心与底物相互作用的过渡态；含有该结构的肽序列，有可能成为研究肽类BACE1抑制剂的另一途径. 应用Autodock 4将所合成化合物与BACE1进行对接，结合体外活性测试结果对构效关系进行了初步探讨. 先导化合物及目标肽用固相法合成，经RP-HPLC测定纯度、ESI-MS确定相对分子量.

Synthesis and Activity of BACE1 Inhibitors with New Core Structure

KMI-008 is a well-known lead compound in the design of potent BACE1 inhibitors, in which Pns is the core structure involved in several important interactions with BACE1. In our research for new potent BACE1 inhibitors, 4-OH or 4-NH2-substituted proline was used to study the better conformation of these two function groups. Further introduction of phenyl group by L-phenylalanine increased activity significantly. It seems that L-Phe-D-Pro could be an alternative core structure in the design of new BACE1 inhibitors. Structure-activity relationships of the BACE1 inhibitors were studied. All the peptides were synthesized by solid phase synthesis and characterized with ESI-MS.