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.

Autor:	Nguyen TT; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Ding D; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Wolter WR; Freimann Life Sciences Center and Department of Biological Sciences , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Pérez RL; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Champion MM; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Mahasenan KV; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Hesek D; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Lee M; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Schroeder VA; Freimann Life Sciences Center and Department of Biological Sciences , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Jones JI; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Lastochkin E; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Rose MK; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Peterson CE; Center for Wound Healing , Elkhart General Hospital , Elkhart , Indiana 46514 , United States., Suckow MA; Freimann Life Sciences Center and Department of Biological Sciences , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Mobashery S; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States., Chang M; Department of Chemistry and Biochemistry , University of Notre Dame , Notre Dame , Indiana 46556 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Oct 11; Vol. 61 (19), pp. 8825-8837. Date of Electronic Publication: 2018 Sep 27.
DOI:	10.1021/acs.jmedchem.8b01005
Abstrakt:	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.
Databáze:	MEDLINE
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