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
  • 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. [email protected].
  • 13. Department of Surgery and Medicine, University of Melbourne, Melbourne, VIC, Australia. [email protected].
  • 14. School of Science, RMIT University, GPO Box 2476, Melbourne, VIC, 3001, Australia. [email protected].
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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