Recent antimalarial drug discovery has been a race to produce new medicines that overcome emerging drug resistance, whilst considering safety and improving dosing convenience. Discovery efforts have yielded a variety of new molecules, many with novel modes of action, and the most advanced are in late-stage clinical development. These discoveries have led to a deeper understanding of how antimalarial drugs act, the identification of a new generation of drug targets, and multiple structure-based chemistry initiatives. The limited pool of funding means it is vital to prioritize new drug candidates. They should exhibit high potency, a low propensity for resistance, a pharmacokinetic profile that favours infrequent dosing, low cost, preclinical results that demonstrate safety and tolerability in women and infants, and preferably the ability to block Plasmodium transmission to Anopheles mosquito vectors. In this Review, we describe the approaches that have been successful, progress in preclinical and clinical development, and existing challenges. We illustrate how antimalarial drug discovery can serve as a model for drug discovery in diseases of poverty.
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The University of Cape Town, Medicines for Malaria Venture (MMV09_0002, RD-17–0004 and RD-18–0001), Bill & Melinda Gates Foundation (OPP1066878 and INV-040482), South African Medical Research Council (SAMRC), Strategic Health Innovation Partnerships (SHIP) unit of the SAMRC, South African Technology Innovation Agency (TIA), Celgene, Merck KGaA (M3409), National Institutes of Health (NIH, 1R01AI152092–01 and 5R01 AI143521–04), and South African Research Chairs Initiative of the Department of Science and Innovation (DSI), administered through the South African National Research Foundation (NRF), are gratefully acknowledged for support (K.C. and K.W.). K.C. is the Neville Isdell Chair in African-centric Drug Discovery and Development and thanks Neville Isdell for generously funding the Chair. J.L.S.-N. is supported by the Bill & Melinda Gates Foundation (INV-007124) and the NIH (1 R01 AI151639 01). D.A.F. gratefully acknowledges funding from the Medicines for Malaria Venture (RD008/15), the Bill & Melinda Gates Foundation (INV-033538), the US Department of Defense (E01 W81XWH2210520) and the NIH (R01 AI109023, R37 AI050234, R01 AI124678). E.A.W. is supported by grants from the NIH (R01 AI152533) and the Bill & Melinda Gates Foundation (OPP1054480). The authors acknowledge Tim Wells for critically reviewing this manuscript.
J.N.B. is employed by the Medicines for Malaria Venture, which has a stake in developing many of the drugs cited in this Review.
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Siqueira-Neto, J.L., Wicht, K.J., Chibale, K. et al. Antimalarial drug discovery: progress and approaches. Nat Rev Drug Discov 22, 807–826 (2023). https://doi.org/10.1038/s41573-023-00772-9