Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template

Gall, Flavio; Hohl, Deborah; Frasson, David; Wermelinger, Tobias; Mittl, Peer R. E.; Sievers, Martin; Riedl, Rainer

doi:10.1002/anie.201812348

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 1521-3773
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).
URI:	https://digitalcollection.zhaw.ch/handle/11475/21751
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

Files in This Item:

There are no files associated with this item.

Show full item record

Gall, F., Hohl, D., Frasson, D., Wermelinger, T., Mittl, P. R. E., Sievers, M., & Riedl, R. (2019). Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template. Angewandte Chemie: International Edition, 58(12), 4051–4055. https://doi.org/10.1002/anie.201812348

Gall, F. et al. (2019) ‘Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template’, Angewandte Chemie: International Edition, 58(12), pp. 4051–4055. Available at: https://doi.org/10.1002/anie.201812348.

F. Gall et al., “Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template,” Angewandte Chemie: International Edition, vol. 58, no. 12, pp. 4051–4055, Jan. 2019, doi: 10.1002/anie.201812348.

GALL, Flavio, Deborah HOHL, David FRASSON, Tobias WERMELINGER, Peer R. E. MITTL, Martin SIEVERS und Rainer RIEDL, 2019. Drug design inspired by nature : crystallographic detection of an auto‐tailored protease inhibitor template. Angewandte Chemie: International Edition. 7 Januar 2019. Bd. 58, Nr. 12, S. 4051–4055. DOI 10.1002/anie.201812348

Gall, Flavio, Deborah Hohl, David Frasson, Tobias Wermelinger, Peer R. E. Mittl, Martin Sievers, and Rainer Riedl. 2019. “Drug Design Inspired by Nature : Crystallographic Detection of an Auto‐Tailored Protease Inhibitor Template.” Angewandte Chemie: International Edition 58 (12): 4051–55. https://doi.org/10.1002/anie.201812348.

Gall, Flavio, et al. “Drug Design Inspired by Nature : Crystallographic Detection of an Auto‐Tailored Protease Inhibitor Template.” Angewandte Chemie: International Edition, vol. 58, no. 12, Jan. 2019, pp. 4051–55, https://doi.org/10.1002/anie.201812348.