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

Citation:

J. Shirian, V. Arkadash, I. Cohen, T. Sapir, E. S. Radisky, N. Papo, and J. M. Shifman. 2018. “Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14.” FEBS Lett, 592, Pp. 1122-1134.

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.

Notes:

Shirian, JasonArkadash, ValeriaCohen, ItaySapir, TamilaRadisky, Evette SPapo, NivShifman, Julia MengR01 CA154387/CA/NCI NIH HHS/R21 CA205471/CA/NCI NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tEnglandFEBS Lett. 2018 Apr;592(7):1122-1134. doi: 10.1002/1873-3468.13016. Epub 2018 Mar 12.