Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14

FEBS Letters
Jason ShirianJulia M Shifman

Abstract

MMP-14 and MMP-9 are two well-established cancer targets for which no specific clinically relevant inhibitor is available. Using a powerful combination of computational design and yeast surface display technology, we engineered such an inhibitor starting from a nonspecific MMP inhibitor, N-TIMP2. The engineered purified N-TIMP2 variants showed enhanced specificity toward MMP-14 and MMP-9 relative to a panel of off-target MMPs. MMP-specific N-TIMP2 sequence signatures were obtained that could be understood from the structural perspective of MMP/N-TIMP2 interactions. Our MMP-9 inhibitor exhibited 1000-fold preference for MMP-9 vs. MMP-14, which is likely to translate into significant differences under physiological conditions. Our results provide new insights regarding evolution of promiscuous proteins and optimization strategies for design of inhibitors with single-target specificities.

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Citations

Nov 9, 2018·Antibody Therapeutics·Tyler LopezXin Ge
Feb 19, 2020·Eye & Contact Lens·Emery C JamersonYasmine M El Sayed
Sep 15, 2020·Expert Opinion on Drug Discovery·Thomas Fischer, Rainer Riedl
Oct 17, 2018·Proceedings of the National Academy of Sciences of the United States of America·Justin M JensonAmy E Keating
May 30, 2020·Cells·Maryam Raeeszadeh-SarmazdehBrianne G Hritz
Dec 12, 2018·PloS One·Aaro KasurinenCaj Haglund
Jan 1, 2021·International Journal of Molecular Sciences·Stephan Niland, Johannes A Eble
Aug 27, 2021·Protein Engineering, Design & Selection : PEDS·Alessandro Bonadio, Julia M Shifman

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