Publication type: Article in scientific journal
Type of review: Peer review (publication)
Title: Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template
Authors: Gall, Flavio
Hohl, Deborah
Frasson, David
Wermelinger, Tobias
Mittl, Peer R. E.
Sievers, Martin
Riedl, Rainer
et. al: No
DOI: 10.1002/anie.201812348
Published in: Angewandte Chemie: International Edition
Volume(Issue): 58
Issue: 12
Page(s): 4051
Pages to: 4055
Issue Date: 7-Jan-2019
Publisher / Ed. Institution: Wiley
ISSN: 1433-7851
Language: English
Subjects: Drug design; Medicinal chemistry; Peptidomimetics; Structural biology; Structure-activity relationship; Binding sites; Crystallography; Cyclization; Matrix metalloproteinase 13; Matrix metalloproteinase inhibitors; Molecular dynamics simulation; Cyclic peptides; Peptidomimetics; Protease inhibitors; Tissue inhibitor of metalloproteinases; X-Ray
Subject (DDC): 615: Pharmacology and therapeutics
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 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).
Fulltext version: Published version
License (according to publishing contract): Licence according to publishing contract
Departement: Life Sciences and Facility Management
Organisational Unit: Institute of Chemistry and Biotechnology (ICBT)
Appears in collections:Publikationen Life Sciences und Facility Management

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