Drug Design Inspired by Nature: Crystallographic Detection of an Auto‐Tailored Protease Inhibitor Template. Issue 12 (6th February 2019)

• Record Type: Journal Article
• Authors: Gall, Flavio M.; Hohl, Deborah; Frasson, David; Wermelinger, Tobias; Mittl, Peer R. E.; Sievers, Martin; Riedl, Rainer
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 12(2019)
• Page Start: 4051
• Page End: 4055
• Publication Date: 2019-02-06
• Subjects: drug design -- medicinal chemistry -- peptidomimetics -- structural biology -- structure–activity relationship; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201812348
• Languages: English
• ISSNs: 1433-7851

Abstract

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 ). Abstract : Closing the circle : The crystallographic discovery of a peptide generated through partial self‐degradation of the therapeutic target paves the way for the de novo generation of a potent and selective cyclic peptidomimetic of the endogenous tissue inhibitors of metalloproteinases (TIMPs).