Directed evolution of metalloproteinase inhibitor TIMP-1 for selective inhibition of MMP-9 exploits catalytic and fibronectin domain interactions.

ABSTRACT: Matrix metalloproteinase-9 (MMP-9) is a critical enzyme involved in extracellular matrix degradation and is strongly implicated in many diseases, including triple-negative breast cancer and other poor prognosis cancers. Selective inhibition of MMP-9 is therefore a promising therapeutic strategy. However, development of MMP inhibitors has been hindered by challenges in achieving specificity, with past efforts failing in clinical trials due to off-target effects and associated toxicity. Here, we present a novel approach to overcoming these challenges by engineering tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural broad-spectrum MMP inhibitor, to achieve enhanced specificity and affinity for MMP-9. We demonstrate that TIMP-1 can be strategically engineered to selectively inhibit M

SUBMITTER: Shoari A 

PROVIDER: S-EPMC12206030 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature