|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|
Mittl, Peer R. E.
|Published in:||Angewandte Chemie: International Edition|
|Publisher / Ed. Institution:||Wiley|
|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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