Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Nat Commun. 2023 Jul 19;14(1):4356. doi: 10.1038/s41467-023-40043-0.
The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110's benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110's benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.
细胞质大型 GTP 酶，与动力蛋白相关蛋白 1（Drp1），介导生理和病理线粒体裂变。细胞应激触发 Drp1 与线粒体 Fis1 结合，随后导致线粒体片段化、ROS 产生、代谢崩溃和细胞死亡。因为 Drp1 还通过与线粒体 Mff 结合来介导生理裂变，所以抑制病理性裂变的治疗方法应该不会影响生理线粒体裂变。P110 是 Drp1-Fis1 相互作用的肽抑制剂，可减少神经退行性变、缺血和败血症的多种模型中的病理，而不会阻断 Drp1 的生理功能。由于肽具有药代动力学限制，我们着手寻找模拟 P110 益处的小分子。我们将 P110 结合位点映射到 Drp1 上的开关 I 相邻凹槽（SWAG）。筛选 SWAG 结合小分子可识别出 SC9，它可模拟 P110 在细胞和内毒素血症小鼠模型中的益处。我们认为，本研究中发现的 SWAG 结合小分子可能会减轻由 Drp1 介导的病理学以及其他 GTPase 家族成员相关病理学的负担。
