靛红类双功能抑制剂:调控SARS-3CL蛋白酶聚集状态与活性(英文)

doi:10.3866/PKU.WHXB201209143

CORC > 北京大学 > 化学与分子工程学院

	靛红类双功能抑制剂:调控SARS-3CL蛋白酶聚集状态与活性(英文); Isatin Dual Functional Inhibitors: Modulating the Aggregation State and Enzyme Activity of SARS-3CL Proteinase
	周璐 ; 金凤 ; 刘莹 ; 尚尔昌 ; 魏平 ; 李春梅 ; 来鲁华
刊名	物理化学学报
	2012
关键词	靛红类衍生物调控 SARS-3CL蛋白酶二聚双功能抑制剂 Isatin derivative Modulation SARS-3CL proteinase Dimerization Dual functional inhibitor
DOI	10.3866/PKU.WHXB201209143
英文摘要	1-(2-萘甲基)靛红-5-甲酰胺类化合物通过与底物口袋结合来抑制SARS-3CL蛋白酶的活性,而SARS-3CL蛋白酶自身的N端8肽是作用于蛋白二聚界面的抑制剂.本文设计同时占据SARS-3CL蛋白酶底物口袋和二聚界面的双功能抑制剂,通过固相多肽合成方法制备由1-(2-萘甲基)靛红-5-甲酸和N端8肽组成的化合物,得到不同长度连接链的6个目标产物.用显色底物方法测定化合物对SARS-3CL蛋白酶的抑制活性,其中化合物3的活性最高,IC50值(半抑制率)为3.8μmol·L-1,连接偶数甘氨酸的活性明显要好于连接奇数甘氨酸的化合物.用超速离心沉降速率方法研究了化合物3对SARS-3CL蛋白酶聚...; The 1-(2-naphthlmethyl) isatin-5-formamide compounds can inhibit SARS-3CL proteinase by binding to its substrate pocket, while the N-terminal octapeptide of SARS-3CL proteinase was found to act as a dimerization inhibitor. In this work, the dual functional inhibitors which can occupy both substrate pocket of SARS-3CL proteinase and its dimer interface were designed. Six title compounds were gotten by linking 1-(2-naphthlmethyl) isatin-5-formic acid and N-terminal octapeptides using a polyglycine linker through solid-phase peptide synthesis method. The in vitro inhibition activity against SARS-3CL proteinase was measured by continuous colorimetric assay using colorimetric substrate. Compound 3 showed the highest inhibition activity with an IC50 (half maximal inhibitory concentration of a substance) of 3.8 mu mol.L-1. The change of inhibition activity with the linker length was studied. Inhibitors with the even spacers were showed better activity than the odd ones, which could be explained by the angle restriction of peptide bonds. The modulating of the aggregation state and enzyme activity towards SARS-3CL proteinase were studied using sedimentation velocity experiments. Compound 3 was found to not only inhibit the enzyme activity of SARS-3CL proteinase, but also shift the monomer-dimer equilibrium of the enzyme. The integrated control result is inhibiting SARS-3CL proteinase dimer formation. This work provides an example of using synthesized compounds to study enzyme activity regulation mechanism.; http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000310181300023&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701 ; SCI(E); 中文核心期刊要目总览(PKU); 中国科技核心期刊(ISTIC); 中国科学引文数据库(CSCD); 0; 10; 2418-2422; 28
语种	中文
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/85370]
专题	化学与分子工程学院生命科学学院
推荐引用方式 GB/T 7714	周璐,金凤,刘莹,等. 靛红类双功能抑制剂:调控SARS-3CL蛋白酶聚集状态与活性(英文), Isatin Dual Functional Inhibitors: Modulating the Aggregation State and Enzyme Activity of SARS-3CL Proteinase[J]. 物理化学学报,2012.
APA	周璐.,金凤.,刘莹.,尚尔昌.,魏平.,...&来鲁华.(2012).靛红类双功能抑制剂:调控SARS-3CL蛋白酶聚集状态与活性(英文).物理化学学报.
MLA	周璐,et al."靛红类双功能抑制剂:调控SARS-3CL蛋白酶聚集状态与活性(英文)".物理化学学报 (2012).