2. Academic Validation
  3. A novel small molecule inhibitor of human Drp1

A novel small molecule inhibitor of human Drp1

  • Sci Rep. 2022 Dec 13;12(1):21531. doi: 10.1038/s41598-022-25464-z.
Ayeshah A Rosdah 1 2 3,  Belinda M Abbott 4,  Christopher G Langendorf 1,  Yali Deng 1 3,  Jia Q Truong 5,  Helen M M Waddell 6,  Naomi X Y Ling 1,  William J Smiles 1,  Lea M D Delbridge 6,  Guei-Sheung Liu 3 7 8,  Jonathan S Oakhill 1 9,  Shiang Y Lim 1 3 10 11,  Jessica K Holien 12 13 14
Affiliations

Affiliations

  • 1 St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
  • 2 Faculty of Medicine, Universitas Sriwijaya, Palembang, Indonesia.
  • 3 Department of Surgery and Medicine, University of Melbourne, Melbourne, VIC, Australia.
  • 4 Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.
  • 5 School of Science, RMIT University, GPO Box 2476, Melbourne, VIC, 3001, Australia.
  • 6 Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia.
  • 7 Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.
  • 8 Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
  • 9 Australian Catholic University, Fitzroy, VIC, Australia.
  • 10 Drug Discovery Biology, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.
  • 11 National Heart Centre, National Heart Research Institute Singapore, Singapore, Singapore.
  • 12 St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia. jessica.holien@rmit.edu.au.
  • 13 Department of Surgery and Medicine, University of Melbourne, Melbourne, VIC, Australia. jessica.holien@rmit.edu.au.
  • 14 School of Science, RMIT University, GPO Box 2476, Melbourne, VIC, 3001, Australia. jessica.holien@rmit.edu.au.
PMID: 36513726 DOI: 10.1038/s41598-022-25464-z
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.

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