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

Jason Shirian; Valeria Arkadash; Itay Cohen; Tamila Sapir; Evette S. Radisky; Niv Papo; Julia M. Shifman

doi:10.1002/1873-3468.13016

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

Jason Shirian, Valeria Arkadash, Itay Cohen, Tamila Sapir, Evette S. Radisky, Niv Papo^*, Julia M. Shifman

^*Corresponding author for this work

Department of Biological Chemistry

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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.

Original language	English
Pages (from-to)	1122-1134
Number of pages	13
Journal	FEBS Letters
Volume	592
Issue number	7
DOIs	https://doi.org/10.1002/1873-3468.13016
State	Published - Apr 2018

Bibliographical note

Publisher Copyright:
© 2018 Federation of European Biochemical Societies

Keywords

binding specificity
matrix metalloproteinase inhibitors
protein engineering
protein–protein interactions

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/1873-3468.13016

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title = "Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14",

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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author = "Jason Shirian and Valeria Arkadash and Itay Cohen and Tamila Sapir and Radisky, {Evette S.} and Niv Papo and Shifman, {Julia M.}",

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doi = "10.1002/1873-3468.13016",

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AU - Papo, Niv

AU - Shifman, Julia M.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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