DRP1i27 is a Potent Human Drp1 Inhibitor

Dynamin-related protein 1 (Drp1) is a GTPase that is the fundamental component and regulator of mitochondrial fission. It consists of a GTPase and GTPase effector domain. Mitochondrial fission promotes mitophagy (the breakdown and recycling of damaged mitochondria). However, fission could lead to mitochondrial fragmentation which facilitates the production of reactive oxygen species (ROS). Then, the overactive fission would destroy normal biochemical processes inside of cells, which also influences calcium flux. Therefore, Drp1 is related to various pathways and progresses, such as cell division, apoptosis, and necrosis.

It has been proved that Drp1 inhibitor, Mdivi-1, shows cytoprotective effects in various cell types and injury models such as ischemia-reperfusion injury, and Doxorubicin-induced cytotoxicity. Thus, the inhibition of Drp1 has been used to treat many diseases.

DRP1i27 is a potent inhibitor of human Drp1.

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From: Rosdah AA, et al. Sci Rep. 2022 Dec 13;12(1):21531.

DRP1i27 binds to the GTPase site of Drp1, with hydrogen bonds to Gln34 and Asp218. It has a binding affinity of 286 µM in the SPR assay and a KD value of 190 µM via the MST assay. Also, DRP1i27 (5-50 µM) could inhibit the conversion of GTP to GDP. Importantly, this inhibitor had no significant effect on Drp1 knock-out mouse embryonic fibroblasts (MEFs). DRP1i27 (0-50 µM) was able to increase cellular networks of mitochondria in human and mouse fibroblasts in a Drp1-dependent manner.

Besides, DRP1i27 (50 µM) showed a significant reduction of cell death in murine atrial HL-1 cells during simulated ischemia-reperfusion injury compared to the vehicle control (15.17 ± 3.67% in 50 µM DRP1i27 vs. 29.55 ± 5.45% in DMSO, p ≤ 0.05). Treatment with DRP1i27 significantly reduced the cytotoxicity induced by 5 µM of Doxorubicin.

In conclusion, DRP1i27 is a potent Drp1 inhibitor that has the potential to research ischemia-reperfusion injury.

Reference:

Rosdah AA, et al. Sci Rep. 2022 Dec 13;12(1):21531.