Drug design inspired by Nature: Crystallographic detection of auto‐tailored protease inhibitor template

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, auto‐tailored by the therapeutic target MMP‐13 through partial self‐degradation and the 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 anti‐cancer targets MMP‐2 (IC50: 170 nM) and MMP‐9 (IC50: 140 nM).

from A via a.sfakia on Inoreader http://bit.ly/2Rgh7RP