Validation of Matrix Metalloproteinase-9 (MMP-9) as a Novel Target for Treatment of Diabetic Foot Ulcers in Humans and Discovery of a Potent and Selective Small-Molecule MMP-9 Inhibitor That Accelerates Healing

Trung T. Nguyen, Derong Ding, William R. Wolter, Rocio L. Pérez, Matthew M. Champion, Kiran V. Mahasenan, Dusan Hesek, Mijoon Lee, Valerie A. Schroeder, Jeffrey I. Jones, Elena Lastochkin, Margaret K. Rose, Charles E. Peterson, Mark A. Suckow, Shahriar Mobashery, Mayland Chang

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

Diabetic foot ulcers (DFUs) are a significant health problem. A single existing FDA-approved drug for this ailment, becaplermin, is not standard-of-care. We previously demonstrated that upregulation of active matrix metalloproteinase (MMP)-9 is the reason that the diabetic wound in mice is recalcitrant to healing and that MMP-8 participates in wound repair. In the present study, we validate the target MMP-9 by identifying and quantifying active MMP-8 and MMP-9 in human diabetic wounds using an affinity resin that binds exclusively to the active forms of MMPs coupled with proteomics. Furthermore, we synthesize and evaluate enantiomerically pure (R)- and (S)-ND-336, as inhibitors of the detrimental MMP-9, and show that the (R)-enantiomer has superior efficacy in wound healing over becaplermin. Our results reveal that the mechanisms of pathology and repair are similar in diabetic mice and diabetic humans and that (R)-ND-336 holds promise for the treatment of DFUs as a first-in-class therapeutic.

Original languageEnglish
Pages (from-to)8825-8837
Number of pages13
JournalJournal of Medicinal Chemistry
Volume61
Issue number19
DOIs
StatePublished - Oct 11 2018

Bibliographical note

Publisher Copyright:
Copyright © 2018 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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