Targeting Matrix Metalloproteinases: Design of a Bifunctional Inhibitor for Presentation by Tumour‐Associated Galectins

Abstract

A new strategy to exploit galectin presence to target matrix metalloproteinases (MMPs) is presented. A bifunctional conjugate with lactose and an inhibitor for MMPs is able to bind MMP and Gal-3 simultaneously. This compound might allow the lectin to attract the MMP inhibitor to the tumour site and to block protumoural activities of the lectin at the same time.

Galectin-3 Induces a Pro-degradative/inflammatory Gene Signature in Human Chondrocytes, Teaming Up with Galectin-1 in Osteoarthritis Pathogenesis

“…Considering glycosylation, the possibility to keep local NF-κB activation at bay by involving inhibitory receptors dampening inflammatory responses, as seen in bacterial infections53, can open a promising route for intervention with disease progression. Such a beneficial outcome may also be envisioned by using bifunctional compounds targeting and blocking galectins and MMPs54, their local efficiency most properly assessed histochemically55.…”

Quantum Dot-Based Probes for Labeling and Imaging of Cells that Express Matrix Metalloproteinases

“…The MMPI selected to conjugate to the surface of the QDs, 1 , 23 is structurally related to NNGH (Scheme 1) and displays a triethylene glycol residue linked to sulfonamidic nitrogen (Scheme 1). This polar linker accounts for a good solubility in water of the inhibitor.…”

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…Compound 7 ( Figure 5) is the progenitoro fm any potent MMP inhibitors and is accommodated in as imilarw ay at the catalytic center of MMP-12. [68][69][70][71] Ac omparison of X-ray structuresa nd solution structures of 7 in MMP-12 revealed high similarity of the enzyme,w ith differences mainly in the loop region;t hus indicating dynamic behavior of the loops in solution. [68] The hypothesis that the simultaneous inhibition of MMP-1 by broad-spectrum inhibitors could be the reason for the adverse side effects [60] ignited the search for MMP inhibitors that spared MMP-1.…”

“…The para ‐methoxy‐substituted phenyl ring is located at the entry of the S1′ pocket, but does not penetrate it. Compound 7 (Figure ) is the progenitor of many potent MMP inhibitors and is accommodated in a similar way at the catalytic center of MMP‐12 . A comparison of X‐ray structures and solution structures of 7 in MMP‐12 revealed high similarity of the enzyme, with differences mainly in the loop region; thus indicating dynamic behavior of the loops in solution …”