Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
Redox Biol. 2023 Apr;60:102611. doi: 10.1016/j.redox.2023.102611. Epub 2023 Jan 18.
NADPH oxidases (NOX's), and the reactive oxygen species (ROS) they produce, play an important role in host defense, thyroid hormone synthesis, apoptosis, gene regulation, angiogenesis and other processes. However, overproduction of ROS by these enzymes is associated with cardiovascular disease, fibrosis, traumatic brain injury (TBI) and other diseases. Structural similarities between NOX's have complicated development of specific inhibitors. Here, we report development of NCATS-SM7270, a small molecule optimized from GSK2795039, that inhibited NOX2 in primary human and mouse granulocytes. NCATS-SM7270 specifically inhibited NOX2 and had reduced inhibitory activity against xanthine oxidase in vitro. We also studied the role of several NOX isoforms during mild TBI (mTBI) and demonstrated that NOX2 and, to a lesser extent, NOX1 deficient mice are protected from mTBI pathology, whereas injury is exacerbated in NOX4 knockouts. Given the pathogenic role played by NOX2 in mTBI, we treated mice transcranially with NCATS-SM7270 after injury and revealed a dose-dependent reduction in mTBI induced cortical cell death. This inhibitor also partially reversed cortical damage observed in NOX4 deficient mice following mTBI. These data demonstrate that NCATS-SM7270 is an improved and specific inhibitor of NOX2 capable of protecting mice from NOX2-dependent cell death associated with mTBI.
NADPH 氧化酶（NOXs）及其产生的活性氧（ROS）在宿主防御、甲状腺激素合成、细胞凋亡、基因调控、血管生成和其他过程中发挥着重要作用。然而，这些酶产生的 ROS 过量与心血管疾病、纤维化、创伤性脑损伤（TBI）和其他疾病有关。NOXs 之间的结构相似性使得特异性抑制剂的开发变得复杂。在这里，我们报告了 NCATS-SM7270 的开发，这是一种从小分子 GSK2795039 优化而来的化合物，可抑制原代人类和小鼠嗜中性粒细胞中的 NOX2。NCATS-SM7270 特异性抑制 NOX2，对黄嘌呤氧化酶的抑制活性降低。我们还研究了几种 NOX 同工型在轻度 TBI（mTBI）中的作用，并证明 NOX2 和（程度较小）NOX1 缺陷小鼠对 mTBI 病理有保护作用，而 NOX4 敲除小鼠的损伤则加剧。鉴于 NOX2 在 mTBI 中的致病作用，我们在损伤后通过颅穿向小鼠给予 NCATS-SM7270，并发现皮质细胞死亡与 mTBI 诱导的剂量依赖性降低。该抑制剂还部分逆转了 mTBI 后 NOX4 缺陷小鼠观察到的皮质损伤。这些数据表明，NCATS-SM7270 是一种改进的、特异性抑制 NOX2 的抑制剂，能够保护小鼠免受与 mTBI 相关的 NOX2 依赖性细胞死亡。
