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

Journal article

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.

Authors: Edgar, RCS; Malcolm, TR; Siddiqui, G; Giannangelo, C; Counihan, NA

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Microbiology
• Journal: mBio
• Volume: 16
• Issue: 6
• Article number: e00966-24
• Place of publication: United States
• Publication date: 2024-05-08
• Acceptance date: 2024-04-08
• DOI: 10.1128/mbio.00966-24
• EISSN: 2150-7511
• Pmid: 38717141
• Language: English
• Keywords: Plasmodium falciparum; Plasmodium vivax; malaria; drug resistance; aminopeptidase