Mitobridge (An Astellas Company), Cambridge, Massachusetts 02138, United States.
Syngene International Limited, Bangalore, Karnataka 560099, India.
J Med Chem. 2022 Jul 14;65(13):9418-9446. doi: 10.1021/acs.jmedchem.2c00688. Epub 2022 Jun 28.
CD38 is one of the major nicotinamide adenine dinucleotide (NAD)- and nicotinamide adenine dinucleotide phosphate (NADP)-consuming enzymes in mammals. NAD, NADP, and their reduced counterparts are essential coenzymes for numerous enzymatic reactions, including the maintenance of cellular and mitochondrial redox balance. CD38 expression is upregulated in age-associated inflammation as well as numerous metabolic diseases, resulting in cellular and mitochondrial dysfunction. Recent literature studies demonstrate that CD38 is activated upon ischemia/reperfusion (I/R), leading to a depletion of NADP, which results in endothelial damage and myocardial infarction in the heart. Despite increasing evidence of CD38 involvement in various disease states, relatively few CD38 enzymatic inhibitors have been reported to date. Herein, we describe a CD38 enzymatic inhibitor (, IC = 3 nM against murine CD38) that inhibits CD38 in assay. Mice treated with show strong protection from myocardial damage upon cardiac I/R injury compared to those treated with NAD precursors (nicotinamide riboside) or the known CD38 inhibitor, .
CD38 是哺乳动物中主要的烟酰胺腺嘌呤二核苷酸 (NAD) 和烟酰胺腺嘌呤二核苷酸磷酸 (NADP) 消耗酶之一。NAD、NADP 及其还原形式是许多酶反应所必需的辅酶，包括维持细胞和线粒体氧化还原平衡。CD38 的表达在与年龄相关的炎症以及许多代谢疾病中上调，导致细胞和线粒体功能障碍。最近的文献研究表明，CD38 在缺血/再灌注 (I/R) 后被激活，导致 NADP 耗竭，从而导致心脏内皮损伤和心肌梗死。尽管越来越多的证据表明 CD38 参与了各种疾病状态，但迄今为止报道的 CD38 酶抑制剂相对较少。本文描述了一种 CD38 酶抑制剂（对鼠源 CD38 的 IC = 3 nM），该抑制剂在 测定中抑制 CD38。与用 NAD 前体（烟酰胺核糖苷）或已知的 CD38 抑制剂 治疗的小鼠相比，用 治疗的小鼠在心脏 I/R 损伤时显示出对心肌损伤的强烈保护作用。
