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.
Bibliographical noteFunding Information:
T.T.N. is a Ruth L. Kirschtein National Research Service Award Fellow of the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, supported by Training Grant T32 GM075762 from the National Institutes of Health. This work was supported by the American Diabetes Association Pathway to Stop Diabetes Grant 1-15-ACN-06.