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

  • J Med Chem. 2018 Oct 11;61(19):8825-8837. doi: 10.1021/acs.jmedchem.8b01005.
Trung T Nguyen  1 ,  Derong Ding  1 ,  William R Wolter  2 ,  Rocio L Pérez  1 ,  Matthew M Champion  1 ,  Kiran V Mahasenan  1 ,  Dusan Hesek  1 ,  Mijoon Lee  1 ,  Valerie A Schroeder  2 ,  Jeffrey I Jones  1 ,  Elena Lastochkin  1 ,  Margaret K Rose  1 ,  Charles E Peterson  3 ,  Mark A Suckow  2 ,  Shahriar Mobashery  1 ,  Mayland Chang  1
Affiliations
  • 1. Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States.
  • 2. Freimann Life Sciences Center and Department of Biological Sciences , University of Notre Dame , Notre Dame , Indiana 46556 , United States.
  • 3. Center for Wound Healing , Elkhart General Hospital , Elkhart , Indiana 46514 , United States.
PMID: 30212201 DOI: 10.1021/acs.jmedchem.8b01005
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.

Products