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

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.