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Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template


Gall, Flavio M; Hohl, Deborah; Frasson, David; Wermelinger, Tobias; Mittl, Peer R E; Sievers, Martin; Riedl, Rainer (2019). Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template. Angewandte Chemie Internationale Edition, 58(12):4051-4055.

Abstract

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 β-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 IC of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC : 170 nm) and MMP-9 (IC : 140 nm).

Abstract

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 β-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 IC of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC : 170 nm) and MMP-9 (IC : 140 nm).

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Physical Sciences > Catalysis
Physical Sciences > General Chemistry
Language:English
Date:18 March 2019
Deposited On:06 Sep 2019 08:03
Last Modified:29 Jul 2020 11:15
Publisher:Wiley-VCH Verlag
ISSN:1433-7851
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/anie.201812348
PubMed ID:30615822

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