A novel small molecule inhibitor of human Drp1
Journal article
Rosdah, Ayeshah A., Abbott, Belinda M., Langendorf, Christopher G., Deng, Yali, Truong, Jia Q., Waddell, Helen M. M., Ling, Naomi X. Y., Smiles, William J., Delbridge, Lea M. D., Liu, Guei-Sheung, Oakhill, Jonathan S., Lim, Shiang Y. and Holien, Jessica K.. (2022). A novel small molecule inhibitor of human Drp1. Scientific Reports. 12(1), p. Article 21531. https://doi.org/10.1038/s41598-022-25464-z
Authors | Rosdah, Ayeshah A., Abbott, Belinda M., Langendorf, Christopher G., Deng, Yali, Truong, Jia Q., Waddell, Helen M. M., Ling, Naomi X. Y., Smiles, William J., Delbridge, Lea M. D., Liu, Guei-Sheung, Oakhill, Jonathan S., Lim, Shiang Y. and Holien, Jessica K. |
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Abstract | Mitochondrial dynamin-related protein 1 (Drp1) is a large GTPase regulator of mitochondrial dynamics and is known to play an important role in numerous pathophysiological processes. Despite being the most widely used Drp1 inhibitor, the specificity of Mdivi-1 towards human Drp1 has not been definitively proven and there have been numerous issues reported with its use including off-target effects. In our hands Mdivi-1 showed varying binding affinities toward human Drp1, potentially impacted by compound aggregation. Herein, we sought to identify a novel small molecule inhibitor of Drp1. From an initial virtual screening, we identified DRP1i27 as a compound which directly bound to the human isoform 3 of Drp1 via surface plasmon resonance and microscale thermophoresis. Importantly, DRP1i27 was found to have a dose-dependent increase in the cellular networks of fused mitochondria but had no effect in Drp1 knock-out cells. Further analogues of this compound were identified and screened, though none displayed greater affinity to human Drp1 isoform 3 than DRP1i27. To date, this is the first small molecule inhibitor shown to directly bind to human Drp1. |
Year | 2022 |
Journal | Scientific Reports |
Journal citation | 12 (1), p. Article 21531 |
Publisher | Nature Publishing Group |
ISSN | 2045-2322 |
Digital Object Identifier (DOI) | https://doi.org/10.1038/s41598-022-25464-z |
PubMed ID | 36513726 |
Scopus EID | 2-s2.0-85144157615 |
PubMed Central ID | PMC9747717 |
Open access | Published as ‘gold’ (paid) open access |
Page range | 1-13 |
Funder | St Vincent’s Hospital, Melbourne |
Stafford Fox Medical Research Foundation | |
Operational Infrastructure Support (OIS) Program, Victorian Government | |
Australia Awards Scholarship, Australian Government | |
RMIT University | |
Australian Research Council (ARC) | |
Jack Brockhoff Foundation | |
National Health and Medical Research Council (NHMRC) | |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 13 Dec 2022 |
Publication process dates | |
Accepted | 30 Nov 2022 |
Deposited | 21 Jul 2023 |
ARC Funded Research | This output has been funded, wholly or partially, under the Australian Research Council Act 2001 |
Grant ID | DP220103700 |
JBF-4206 |
https://acuresearchbank.acu.edu.au/item/8z5xy/a-novel-small-molecule-inhibitor-of-human-drp1
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Publisher's version
OA_Rosdah_2022_A_novel_small_molecule_inhibitor_of.pdf | |
License: CC BY 4.0 | |
File access level: Open |
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