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
AuthorsRosdah, 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.
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.

Year2022
JournalScientific Reports
Journal citation12 (1), p. Article 21531
PublisherNature Publishing Group
ISSN2045-2322
Digital Object Identifier (DOI)https://doi.org/10.1038/s41598-022-25464-z
PubMed ID36513726
Scopus EID2-s2.0-85144157615
PubMed Central IDPMC9747717
Open accessPublished as ‘gold’ (paid) open access
Page range1-13
FunderSt 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)
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File Access Level
Open
Output statusPublished
Publication dates
Online13 Dec 2022
Publication process dates
Accepted30 Nov 2022
Deposited21 Jul 2023
ARC Funded ResearchThis output has been funded, wholly or partially, under the Australian Research Council Act 2001
Grant IDDP220103700
JBF-4206
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