PR001955 (Project)

Description:To combat the global burden of malaria, development of new drugs to replace or complement current therapies are 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 haemoglobin digestion in asexual parasites. MMV1557817 can kill sexual stage P. falciparum, is active against murine malaria and did 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 sensitised to the current clinical drug, artemisinin. Overall, these results confirm MMV1557817 as a lead compound for further drug development and highlight the potential of dual inhibition of M1 and M17 as an effective multi-species drug targeting strategy.