Zinc-binding groups modulate selective inhibition of MMPs

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Selective inhibition of matrix metalloproteinases (MMPs) is crucial for treating various pathologies.
• Previous MMP inhibitors (MMPi) faced challenges due to undesired side effects, limiting clinical success.
• Current MMPi primarily achieve selectivity through their peptidomimetic backbone.

Purpose of the Study:

• To explore novel MMPi with selectivity determined by the zinc-binding group (ZBG).
• To investigate the impact of different ZBGs on MMP isoform inhibition.
• To evaluate the in vivo efficacy of ZBG-modified MMPi in a relevant biological model.

Main Methods:

• Synthesized six novel MMPi by appending hydroxypyrone and hydroxypyridinone ZBGs to a common biphenyl backbone.
• Determined in vitro inhibition efficiency (IC50 values) against MMP-1, -2, -3, -7, -8, -9, -12, and -13.
• Utilized computational modeling to explain observed selectivity trends and assessed two potent MMPi in an isolated perfused rat heart model subjected to ischemia reperfusion injury.

Main Results:

• The selectivity profiles of the MMPi varied significantly based on the ZBG.
• Computational modeling provided insights into the observed selectivity trends.
• In the rat heart model, only one of the two tested MMPi demonstrated significant and sustained recovery of contractile function post-injury.

Conclusions:

• The choice of ZBG is a critical determinant of MMPi selectivity and therapeutic potential.
• Novel ZBG-based strategies offer a promising avenue for developing more effective and safer MMP inhibitors.
• ZBG modification can translate into significant improvements in relevant pathophysiological endpoints.