基于卡拉巴汀 B1 的环肽的合成及其二硫键连接与活性研究对登革热 NS2B-NS3 蛋白酶的抑制作用。

Synthesis and disulfide bond connectivity-activity studies of a kalata B1-inspired cyclopeptide against dengue NS2B-NS3 protease.

机构信息

Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.

出版信息

Bioorg Med Chem. 2010 Feb;18(3):1331-6. doi: 10.1016/j.bmc.2009.12.026. Epub 2009 Dec 29.

DOI:10.1016/j.bmc.2009.12.026

PMID:20042339

Abstract

Kalata B1 is a plant protein with remarkable thermal, chemical and enzymatic stability. Its potential applications could be centered on the possibility of using its cyclic structure and cystine knot motif as a scaffold for the design of stable pharmaceuticals. To discover potent dengue NS2B-NS3 protease inhibitors, we have prepared various kalata B1 analogues by varying the amino acid sequence. Mass spectrometric and biochemical investigations of these analogues revealed a cyclopeptide whose two fully oxidized forms are substrate-competitive inhibitors of the dengue viral NS2B-NS3 protease. Both oxidized forms showed potent inhibition with K(i) of 1.39+/-0.35 and 3.03+/-0.75 microM, respectively.

摘要

卡拉他丁 B1 是一种具有显著热稳定性、化学稳定性和酶稳定性的植物蛋白。其潜在应用可能集中在利用其环状结构和半胱氨酸结基序作为设计稳定药物的支架的可能性上。为了发现有效的登革热 NS2B-NS3 蛋白酶抑制剂，我们通过改变氨基酸序列制备了各种卡拉他丁 B1 类似物。对这些类似物的质谱和生化研究揭示了一种环肽，其两种完全氧化形式是登革热病毒 NS2B-NS3 蛋白酶的底物竞争性抑制剂。两种氧化形式均表现出很强的抑制作用，Ki 值分别为 1.39+/-0.35 和 3.03+/-0.75 microM。