2. Academic Validation
  3. On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity

On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity

  • mBio. 2024 Jun 12;15(6):e0096624. doi: 10.1128/mbio.00966-24.
Rebecca C S Edgar 1 2,  Tess R Malcolm 3,  Ghizal Siddiqui 4,  Carlo Giannangelo 4,  Natalie A Counihan 1 2,  Matthew Challis 4,  Sandra Duffy 5,  Mrittika Chowdhury 1 2,  Jutta Marfurt 6,  Madeline Dans 1 2,  Grennady Wirjanata 6,  Rintis Noviyanti 7,  Kajal Daware 3,  Chathura D Suraweera 3,  Ric N Price 6 8 9,  Sergio Wittlin 10 11,  Vicky M Avery 12,  Nyssa Drinkwater 3,  Susan A Charman 13,  Darren J Creek 4,  Tania F de Koning-Ward 1 2,  Peter J Scammells 14,  Sheena McGowan 3
Affiliations

Affiliations

  • 1 School of Medicine, Deakin University, Geelong, Australia.
  • 2 The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia.
  • 3 Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia.
  • 4 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
  • 5 Discovery Biology, Centre for Cellular Phenomics, Griffith University, Nathan, Queensland, Australia.
  • 6 Global Health and Tropical Medicine Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
  • 7 Eijkman Institute for Molecular Biology, Jakarta, Indonesia.
  • 8 Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
  • 9 Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • 10 Swiss Tropical and Public Health Institute, Allschwil, Switzerland.
  • 11 University of Basel, Basel, Switzerland.
  • 12 School of Environment and Science, Griffith Sciences, Griffith University, Nathan, Queensland, Australia.
  • 13 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
  • 14 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
PMID: 38717141 DOI: 10.1128/mbio.00966-24
Abstract

To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound MMV1557817 is a selective, nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. MMV1557817 can kill sexual-stage P. falciparum, is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials. MMV1557817-resistant P. falciparum exhibited a slow growth rate that was quickly outcompeted by wild-type parasites and were sensitized to the current clinical drug, artemisinin. Overall, these results confirm MMV1557817 as a lead compound for further drug development and highlights the potential of dual inhibition of M1 and M17 as an effective multi-species drug-targeting strategy.IMPORTANCEEach year, malaria infects approximately 240 million people and causes over 600,000 deaths, mostly in children under 5 years of age. For the past decade, artemisinin-based combination therapies have been recommended by the World Health Organization as the standard malaria treatment worldwide. Their widespread use has led to the development of artemisinin resistance in the form of delayed Parasite clearance, alongside the rise of partner drug resistance. There is an urgent need to develop and deploy new antimalarial agents with novel targets and mechanisms of action. Here, we report a new and potent antimalarial compound, known as MMV1557817, and show that it targets multiple stages of the malaria Parasite lifecycle, is active in a preliminary mouse malaria model, and has a novel mechanism of action. Excitingly, resistance to MMV15578117 appears to be self-limiting, suggesting that development of the compound may provide a new class of antimalarial.

Keywords

Plasmodium falciparum; Plasmodium vivax; aminopeptidase; drug resistance; malaria.

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