NMS-873 作为一种线粒体氧化磷酸化的双重抑制剂。
NMS-873 functions as a dual inhibitor of mitochondrial oxidative phosphorylation.
机构信息
Calvin University, Department of Chemistry & Biochemistry, 1726 Knollcrest Circle SE, Grand Rapids, MI, 49546, USA.
Calvin University, Department of Chemistry & Biochemistry, 1726 Knollcrest Circle SE, Grand Rapids, MI, 49546, USA.
出版信息
Biochimie. 2021 Jun;185:33-42. doi: 10.1016/j.biochi.2021.03.004. Epub 2021 Mar 13.
Small-molecule inhibitors of enzyme function are critical tools for the study of cell biological processes and for treatment of human disease. Identifying inhibitors with suitable specificity and selectivity for single enzymes, however, remains a challenge. In this study we describe our serendipitous discovery that NMS-873, a compound that was previously identified as a highly selective allosteric inhibitor of the ATPase valosin-containing protein (VCP/p97), rapidly induces aerobic fermentation in cultured human and mouse cells. Our further investigation uncovered an unexpected off-target effect of NMS-873 on mitochondrial oxidative phosphorylation, specifically as a dual inhibitor of Complex I and ATP synthase. This work points to the need for caution regarding the interpretation of cell survival data associated with NMS-873 treatment and indicates that cellular toxicity associated with its use may be caused by both VCP/p97-dependent and VCP/p97-independent mechanisms.
小分子酶功能抑制剂是研究细胞生物学过程和治疗人类疾病的重要工具。然而，针对单一酶识别具有合适特异性和选择性的抑制剂仍然是一个挑战。在这项研究中，我们描述了一个偶然的发现，即 NMS-873 是一种先前被鉴定为含有 valosin 蛋白（VCP/p97）的 ATP 酶的高度选择性别构抑制剂的化合物，可快速诱导培养的人和小鼠细胞进行需氧发酵。我们的进一步研究揭示了 NMS-873 对线粒体氧化磷酸化的意外非靶标作用，特别是作为复合物 I 和 ATP 合酶的双重抑制剂。这项工作表明，在解释与 NMS-873 治疗相关的细胞存活数据时需要谨慎，并表明与 NMS-873 相关的细胞毒性可能是由 VCP/p97 依赖和非 VCP/p97 依赖机制共同引起的。
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