On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity
3
Issued Date
2024-06-12
Resource Type
eISSN
21507511
Scopus ID
2-s2.0-85196053057
Pubmed ID
38717141
Journal Title
mBio
Volume
15
Issue
6
Rights Holder(s)
SCOPUS
Bibliographic Citation
mBio Vol.15 No.6 (2024) , e0096624
Suggested Citation
Edgar R.C.S., Malcolm T.R., Siddiqui G., Giannangelo C., Counihan N.A., Challis M., Duffy S., Chowdhury M., Marfurt J., Dans M., Wirjanata G., Noviyanti R., Daware K., Suraweera C.D., Price R.N., Wittlin S., Avery V.M., Drinkwater N., Charman S.A., Creek D.J., de Koning-Ward T.F., Scammells P.J., McGowan S. On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity. mBio Vol.15 No.6 (2024) , e0096624. doi:10.1128/mbio.00966-24 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/98922
Title
On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity
Author's Affiliation
Mahidol Oxford Tropical Medicine Research Unit
Monash Institute of Pharmaceutical Sciences
Monash University, Centre for Drug Candidate Optimisation
Eijkman Institute for Molecular Biology
Griffith University
Menzies School of Health Research
Universität Basel
Swiss Tropical and Public Health Institute Swiss TPH
Deakin University
Faculty of Medicine, Nursing and Health Sciences
Nuffield Department of Medicine
Monash Institute of Pharmaceutical Sciences
Monash University, Centre for Drug Candidate Optimisation
Eijkman Institute for Molecular Biology
Griffith University
Menzies School of Health Research
Universität Basel
Swiss Tropical and Public Health Institute Swiss TPH
Deakin University
Faculty of Medicine, Nursing and Health Sciences
Nuffield Department of Medicine
Corresponding Author(s)
Other Contributor(s)
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.