(R)-ND-336 as a Therapeutic Agent for Diabetic Wound Healing

Abstract

Approximately 25% of diabetics develop diabetic foot ulcers (DFUs), resulting in 73,000 lower-limb amputations annually in the United States, with one-year prognosis of 50% mortality. While the involvement of matrix metalloproteinases (MMPs) in wound healing has been known, the challenge remained as to which MMP(s) among the 24 known human variants plays a role in the ailment, compounded by the fact that MMPs exist in three forms, the latent, the activated in complex with protein inhibitors TIMPs, and the activated uninhibited form. The first two are catalytically incompetent. With the use of an affinity resin that fishes out only the catalytically competent MMPs from the complex proteome, we identified active MMP-8 and MMP-9 in wounds of db/db mice and determined that MMP-9 is detrimental and that MMP-8 plays a beneficial role in wound healing. To demonstrate parallels in expression profiles in humans, we studied the debridement tissue from diabetic patients using the affinity resin coupled with proteomics. We identified the very same active MMP-8 and -9 in diabetic human wounds, indicating that the mechanisms of pathology and repair are similar in humans and in mice. Twenty-fold higher levels of the detrimental active MMP-9 were found in Wagner grade 1-4 wounds compared to control. These increased levels for MMP-9 are indeed significant, considering that active MMP-9 is a catalyst that contributes to the recalcitrance of wounds to heal. This observation makes MMP-9 an important target for inhibition with translational potential. We report herein that (R)-ND-336, a novel potent and selective inhibitor of MMP-9, accelerates healing of diabetic wounds and holds promise as recourse in treatment of DFUs. We note that NF-κB levels correlate with that of active MMP-9, hence it is a useful biomarker in identification of candidates for the treatment option. Disclosure M. Chang: None.