2. Academic Validation
  3. Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b

Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b

  • Eur J Med Chem. 2024 Oct 3:280:116921. doi: 10.1016/j.ejmech.2024.116921.
Jon Kyle Awalt 1,  Wenyin Su 1,  William Nguyen 1,  Katie Loi 2,  Kate E Jarman 1,  Jocelyn S Penington 1,  Saishyam Ramesh 3,  Kate J Fairhurst 4,  Tomas Yeo 4,  Heekuk Park 5,  Anne-Catrin Uhlemann 5,  Bikash Chandra Maity 6,  Nirupam De 6,  Partha Mukherjee 6,  Arnish Chakraborty 6,  Alisje Churchyard 7,  Mufuliat T Famodimu 8,  Michael J Delves 8,  Jake Baum 9,  Nimisha Mittal 10,  Elizabeth A Winzeler 10,  Anthony T Papenfuss 1,  Mrittika Chowdury 11,  Tania F de Koning-Ward 11,  Alexander G Maier 3,  Giel G van Dooren 3,  Delphine Baud 12,  Stephen Brand 12,  David A Fidock 13,  Paul F Jackson 14,  Alan F Cowman 1,  Madeline G Dans 15,  Brad E Sleebs 16
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • 2 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia.
  • 3 Research School of Biology, The Australian National University, Canberra, 2600, Australia.
  • 4 Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA.
  • 5 Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 6 TCG Lifesciences, Kolkata, West Bengal, 700091, India.
  • 7 Department of Life Sciences, Imperial College London, South Kensington, SW7 2AZ, UK.
  • 8 Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
  • 9 Department of Life Sciences, Imperial College London, South Kensington, SW7 2AZ, UK; School of Biomedical Sciences, University of New South Wales, Sydney, 2031, Australia.
  • 10 School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • 11 School of Medicine, Deakin University, Waurn Ponds, Victoria, 3216, Australia; Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Victoria, 3216, Australia.
  • 12 Medicines for Malaria Venture, Geneva, 1215, Switzerland.
  • 13 Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Columbia University Irving Medical Center, New York, NY, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 14 Global Public Health, Janssen R&D LLC, La Jolla, 92121, USA.
  • 15 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia. Electronic address: dans.m@wehi.edu.au.
  • 16 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia. Electronic address: sleebs@wehi.edu.au.
PMID: 39388903 DOI: 10.1016/j.ejmech.2024.116921
Abstract

Drug resistance against antimalarials is rendering them increasingly ineffective and so there is a need for the development of new antimalarials. To discover new antimalarial chemotypes a phenotypic screen of the Janssen Jumpstarter library against the P. falciparum asexual stage was undertaken, uncovering the cyclopropyl carboxamide structural hit class. Structure-activity analysis revealed that each structural moiety was largely resistant to change, although small changes led to the frontrunner compound, WJM280, which has potent asexual stage activity (EC50 40 nM) and no human cell cytotoxicity. Forward genetics uncovered that cyclopropyl carboxamide resistant parasites have mutations and an amplification in the cytochrome b gene. Cytochrome b was then verified as the target with profiling against cytochrome b drug-resistant parasites and a mitochondrial oxygen consumption assay. Accordingly, the cyclopropyl carboxamide class was shown to have slow-acting asexual stage activity and activity against male gametes and exoerythrocytic forms. Enhancing metabolic stability to attain efficacy in malaria mouse models remains a challenge in the future development of this antimalarial chemotype.

Keywords

Antimalarial; Cytochrome b; Malaria; Mitochondria; Plasmodium.

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