Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to β-secretase
Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to β-secretase作者机构：State Key Laboratory of Drug Research and National Center for Drug Screening Shanghai Institute of Materia Medica Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai China
出 版 物：《Acta Pharmacologica Sinica》 (中国药理学报(英文版))
年 卷 期：2006年第27卷第12期
页 面：1586-1593页
核心收录：
学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 10[医学]
基 金：Project supported by the National Natural Science Foundation of China(№30230400 and 30200341) the State Key Program of Basic Research of China(2004GB 518907)
主 题：β-secretase hydroxyethylene OM99-2 Alzheimer’s disease structure-activity relationship
摘 要：Aim:To develop probes for detecting the binding specificity between β-secretaseand substrate,and provide reliable biological activity data for further researchingencircling substrate-based ***:To prepare the inhibitors,thehydroxyethylene(HE)segment including P1and P1′ was synthesized after multi-step reactions;the combination of all segments was then completed through solidphase *** human β-secretase ectodomain(amino acid resi-dues 1-460)was expressed as a secreted protein with a C-terminal His tag in insectcells using baculovirus infection,and all compounds were evaluated in thisβ-secretase enzyme *** order to understand the interaction in detail,the theoretical methods,namely molecular dynamics(MD)simulation and mo-lecular mechanics-generalized-born surface area(MM-GBSA)analysis,were per-formed on the complex of β-secretase and OM99-2 to obtain the geometrical andenergetical ***:We designed and constructed a positional scan-ning combinatorial library including 16 compounds;all members of the librarywere synthesized based on HE dipeptide ***-activity relationshipstudies at the P4-P1and P1′-P4′ positions led to the discoveries of P and P’sidesbinding specificity and potent inhibitors 14,18,and *** binding free energyon the whole system and every residue were compared to the biological ***:The removal of P4′ yielded inhibitor 22(A3*B2)with highpotency;further truncation of P3′ gave inhibitor 18(A3*B1)with equal activity,implying that the right side of the inhibitors play a less important role and could beeasily simplified,while change on the P side may cause substantial results.
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