Chang Mayland
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
ACS Pharmacol Transl Sci. 2024 Jul 16;7(10):2901-2911. doi: 10.1021/acsptsci.4c00263. eCollection 2024 Oct 11.
Diabetic foot ulcers (DFUs) are a complication of diabetes that have long been neglected. To date, a single drug (becaplermin containing platelet-derived growth factor, PDGF) has been approved by the FDA 27 years ago; however, it is seldom used because of its modest efficacy. The standard-of-care for DFUs is debridement, off-loading, and infection control with antibiotics, with hyperbaric oxygen (HBO) therapy being the treatment of last recourse. The paucity of understanding what accelerates diabetic wound healing results in more than 150,000 lower-limb amputations in the United States every year. A new paradigm for treatment of DFUs is proposed based on the higher levels of active matrix metalloproteinase (MMP)-9 with the more severe and infected human DFUs, and the demonstrated detrimental role of MMP-9 and the beneficial repair role of MMP-8 in diabetic mice. Selective inhibition of MMP-9 with the small molecule ()-ND-336 lowered inflammation, reduced reactive oxygen species (ROS), and increased angiogenesis, without affecting MMP-8 to allow the natural repair mechanisms to take place. ()-ND-336 showed better efficacy than becaplermin in diabetic mice. Becaplermin (PDGF) and HBO therapy work by decreasing MMP-9, but they do not completely suppress MMP-9 activity.
糖尿病足溃疡（DFUs）是一种长期被忽视的糖尿病并发症。迄今为止，一种单一药物（含血小板衍生生长因子PDGF的贝卡普勒明）在27年前已获美国食品药品监督管理局（FDA）批准；然而，由于其疗效一般，很少被使用。DFUs的标准治疗方法是清创、减压以及使用抗生素控制感染，高压氧（HBO）治疗是最后的治疗手段。对促进糖尿病伤口愈合因素的了解不足，导致美国每年有超过15万例下肢截肢。基于在更严重且感染的人类DFUs中活性基质金属蛋白酶（MMP）-9水平较高，以及在糖尿病小鼠中已证实的MMP-9的有害作用和MMP-8的有益修复作用，提出了一种DFUs的新治疗模式。用小分子（）-ND-336选择性抑制MMP-9可减轻炎症、减少活性氧（ROS）并增加血管生成，同时不影响MMP-8，以使自然修复机制得以发挥作用。在糖尿病小鼠中，（）-ND-336显示出比贝卡普勒明更好的疗效。贝卡普勒明（PDGF）和HBO治疗通过降低MMP-9起作用，但它们并未完全抑制MMP-9的活性。
