期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 58, 期 12, 页码 4051-4055出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201812348
关键词
drug design; medicinal chemistry; peptidomimetics; structural biology; structure-activity relationship
资金
- NIGMS [P41-GM103311]
De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective beta-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nM for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC50: 170 nM) and MMP-9 (IC50: 140 nM).
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据