Drug Design Inspired by Nature: Crystallographic Detection of an 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, 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).
['Gall|Flavio M|FM|0000-0001-5243-1521', 'Hohl|Deborah|D|0000-0002-2795-9372', 'Frasson|David|D|0000-0003-0300-0834', 'Wermelinger|Tobias|T|0000-0001-8793-0582', 'Mittl|Peer R E|PRE|', 'Sievers|Martin|M|0000-0002-0207-5319', 'Riedl|Rainer|R|0000-0003-2534-1963']
D001665:Binding Sites D018360:Crystallography, X-Ray D003500:Cyclization D015195:Drug Design D053509:Matrix Metalloproteinase 13 D061965:Matrix Metalloproteinase Inhibitors D056004:Molecular Dynamics Simulation D010456:Peptides, Cyclic D057786:Peptidomimetics D011480:Protease Inhibitors D019714:Tissue Inhibitor of Metalloproteinases
drug design peptidomimetics medicinal chemistry structural biology structure-activity relationship