Antimalarial drug discovery: progress and approaches

Nature Reviews Drug Discovery (2023)Cite this article

Metrics details

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.

This is a preview of subscription content, access via your institution

Access Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

$29.99 / 30 days

cancel any time

Subscribe to this journal

Receive 12 print issues and online access

$189.00 per year

only $15.75 per issue

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Carter, R. & Mendis, K. N. Evolutionary and historical aspects of the burden of malaria. Clin. Microbiol. Rev. 15, 564–594 (2002).

PubMed PubMed Central Google Scholar

Ashley, E. A., Pyae Phyo, A. & Woodrow, C. J. Malaria. Lancet 391, 1608–1621 (2018).

PubMed Google Scholar

Lal, A. A., Rajvanshi, H., Jayswar, H., Das, A. & Bharti, P. K. Malaria elimination: using past and present experience to make malaria-free India by 2030. J. Vector Borne Dis. 56, 60–65 (2019).

PubMed Google Scholar

World Health Organization. World Malaria Report https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022 (2022).

Chandramohan, D. et al. Seasonal malaria vaccination with or without seasonal malaria chemoprevention. N. Engl. J. Med. 385, 1005–1017 (2021).

CAS PubMed Google Scholar

Sinnis, P. & Fidock, D. A. The RTS,S vaccine-a chance to regain the upper hand against malaria? Cell 185, 750–754 (2022).

CAS PubMed Google Scholar

Datoo, M. S. et al. Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years’ follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial. Lancet Infect. Dis. 22, 1728–1736 (2022).

CAS PubMed Google Scholar

Greenwood, B. et al. Combining malaria vaccination with chemoprevention: a promising new approach to malaria control. Malar. J. 20, 361 (2021).

CAS PubMed PubMed Central Google Scholar

Phillips, M. A. et al. Malaria. Nat. Rev. Dis. Primers 3, 17050 (2017).

PubMed Google Scholar

Wicht, K. J., Mok, S. & Fidock, D. A. Molecular mechanisms of drug resistance in Plasmodium falciparum malaria. Annu. Rev. Microbiol. 74, 431–454 (2020).

CAS PubMed PubMed Central Google Scholar

Rasmussen, C., Alonso, P. & Ringwald, P. Current and emerging strategies to combat antimalarial resistance. Expert Rev. Anti Infect. Ther. 20, 353–372 (2022).

CAS PubMed Google Scholar

Achan, J. et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar. J. 10, 144 (2011).

CAS PubMed PubMed Central Google Scholar

White, N. J. Qinghaosu (artemisinin): the price of success. Science 320, 330–334 (2008).

CAS PubMed Google Scholar

Plowe, C. V. Malaria chemoprevention and drug resistance: a review of the literature and policy implications. Malar. J. 21, 104 (2022).

PubMed PubMed Central Google Scholar

van der Pluijm, R. W. et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect. Dis. 19, 952–961 (2019).

PubMed PubMed Central Google Scholar

Dhorda, M., Amaratunga, C. & Dondorp, A. M. Artemisinin and multidrug-resistant Plasmodium falciparum — a threat for malaria control and elimination. Curr. Opin. Infect. Dis. 34, 432–439 (2021).

CAS PubMed PubMed Central Google Scholar

Uwimana, A. et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat. Med. 26, 1602–1608 (2020). Reported the identification of artemisinin partial resistance emerging in African parasites.

CAS PubMed PubMed Central Google Scholar

Uwimana, A. et al. Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study. Lancet Infect. Dis. 21, 1120–1128 (2021).

CAS PubMed PubMed Central Google Scholar

Balikagala, B. et al. Evidence of artemisinin-resistant malaria in Africa. N. Engl. J. Med. 385, 1163–1171 (2021). Reports clinical evidence that mutant Kelch13 alleles emerging independently in Uganda were associated with prolonged parasite clearance half-lives in patients with P. falciparum infection treated with artesunate.

CAS PubMed Google Scholar

Straimer, J., Gandhi, P., Renner, K. C. & Schmitt, E. K. High prevalence of Plasmodium falciparum K13 mutations in Rwanda is associated with slow parasite clearance after treatment with artemether-lumefantrine. J. Infect. Dis. 225, 1411–1414 (2021).

PubMed Central Google Scholar

Tumwebaze, P. K. et al. Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda. Nat. Commun. 13, 6353 (2022).

CAS PubMed PubMed Central Google Scholar

Ariey, F. et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505, 50–55 (2014).

PubMed Google Scholar

Ashley, E. A. et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 371, 411–423 (2014).

PubMed PubMed Central Google Scholar

Siddiqui, F. A., Liang, X. & Cui, L. Plasmodium falciparum resistance to ACTs: emergence, mechanisms, and outlook. Int. J. Parasitol. Drugs Drug Resist. 16, 102–118 (2021).

CAS PubMed PubMed Central Google Scholar

Straimer, J. et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science 347, 428–431 (2015).

CAS PubMed Google Scholar

Siddiqui, F. A. et al. Plasmodium falciparum falcipain-2a polymorphisms in Southeast Asia and their association with artemisinin resistance. J. Infect. Dis. 218, 434–442 (2018).

CAS PubMed PubMed Central Google Scholar

Yang, T. et al. Decreased K13 abundance reduces hemoglobin catabolism and proteotoxic stress, underpinning artemisinin resistance. Cell Rep. 29, 2917–2928 (2019).

CAS PubMed Google Scholar

Birnbaum, J. et al. A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites. Science 367, 51–59 (2020). This study identified the role of proteins (including K13) in ART resistance and their functional association with reduced haemoglobin endocytosis, a mechanism important for ART activation.

CAS PubMed Google Scholar

Posner, G. H. et al. Mechanism-based design, synthesis, and in vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin: the importance of a carbon-centered radical for antimalarial activity. J. Med. Chem. 37, 1256–1258 (1994).

CAS PubMed Google Scholar

Mok, S. et al. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science 347, 431–435 (2015).

CAS PubMed Google Scholar

Hott, A. et al. Artemisinin-resistant Plasmodium falciparum parasites exhibit altered patterns of development in infected erythrocytes. Antimicrob. Agents Chemother. 59, 3156–3167 (2015).

CAS PubMed PubMed Central Google Scholar

Xie, S. C., Ralph, S. A. & Tilley, L. K13, the cytostome, and artemisinin resistance. Trends Parasitol. 36, 533–544 (2020).

CAS PubMed Google Scholar

Reyser, T. et al. Identification of compounds active against quiescent artemisinin-resistant Plasmodium falciparum parasites via the quiescent-stage survival assay (QSA). J. Antimicrob. Chemother. 75, 2826–2834 (2020).

CAS PubMed Google Scholar

Connelly, S. V. et al. Restructured mitochondrial-nuclear interaction in Plasmodium falciparum dormancy and persister survival after artemisinin exposure. mBio 12, e0075321 (2021).

PubMed Google Scholar

Mok, S. et al. Artemisinin-resistant K13 mutations rewire Plasmodium falciparum’s intra-erythrocytic metabolic program to enhance survival. Nat. Commun. 12, 530 (2021).

CAS PubMed PubMed Central Google Scholar

Imwong, M. et al. Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study. Lancet Infect. Dis. 20, 1470–1480 (2020).

CAS PubMed PubMed Central Google Scholar

Stokes, B. H. et al. Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness. eLife 10, e66277 (2021).

CAS PubMed PubMed Central Google Scholar

Stokes, B. H., Ward, K. E. & Fidock, D. A. Evidence of artemisinin-resistant malaria in Africa. N. Engl. J. Med. 386, 1385–1386 (2022). Laboratory P. falciparum Dd2 parasites edited with kelch13 mutations A675V or C469Y (observed in clinical isolates from Africa) alone showed only marginally reduced susceptibility to dihydroartemisinin, suggesting that high-level resistance to treatment with an artemisinin derivative must include additional mutations.

PubMed PubMed Central Google Scholar

Demas, A. R. et al. Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility. Proc. Natl Acad. Sci. USA 115, 12799–12804 (2018).

CAS PubMed PubMed Central Google Scholar

Sharma, A. I. et al. Genetic background and PfKelch13 affect artemisinin susceptibility of PfCoronin mutants in Plasmodium falciparum. PLoS Genet. 16, e1009266 (2020).

CAS PubMed PubMed Central Google Scholar

Henrici, R. C., van Schalkwyk, D. A. & Sutherland, C. J. Modification of pfap2mu and pfubp1 markedly reduces ring-stage susceptibility of Plasmodium falciparum to artemisinin in vitro. Antimicrob. Agents Chemother. https://doi.org/10.1128/AAC.01542-19 (2019).

Article PubMed PubMed Central Google Scholar

Amambua-Ngwa, A. et al. Major subpopulations of Plasmodium falciparum in sub-Saharan Africa. Science 365, 813–816 (2019). Important analysis of genetic population of P. falciparum clinical isolate samples in African continent revealing shared genomic haplotypes associated with antimalarial resistance.

CAS PubMed Google Scholar

Masserey, T. et al. The influence of biological, epidemiological, and treatment factors on the establishment and spread of drug-resistant Plasmodium falciparum. eLife https://doi.org/10.7554/eLife.77634 (2022).

Article PubMed PubMed Central Google Scholar

Imwong, M. et al. Evolution of multidrug resistance in Plasmodium falciparum: a longitudinal study of genetic resistance markers in the Greater Mekong subregion. Antimicrob. Agents Chemother. 65, e0112121 (2021).

PubMed Google Scholar

Amato, R. et al. Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study. Lancet Infect. Dis. 17, 164–173 (2017).

CAS PubMed Google Scholar

Witkowski, B. et al. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study. Lancet Infect. Dis. 17, 174–183 (2017).

CAS PubMed PubMed Central Google Scholar

Chugh, M. et al. Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium falciparum. Proc. Natl Acad. Sci. USA 110, 5392–5397 (2013).

CAS PubMed PubMed Central Google Scholar

Rathore, I. et al. Activation mechanism of plasmepsins, pepsin-like aspartic proteases from Plasmodium, follows a unique trans-activation pathway. FEBS J. 288, 678–698 (2021).

CAS PubMed Google Scholar

Bopp, S. et al. Plasmepsin II-III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum. Nat. Commun. 9, 1769 (2018).

PubMed PubMed Central Google Scholar

Dhingra, S. K. et al. A variant PfCRT isoform can contribute to Plasmodium falciparum resistance to the first-line partner drug piperaquine. mBio 8, e00303-17 (2017).

PubMed PubMed Central Google Scholar

Ross, L. S. et al. Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine. Nat. Commun. 9, 3314 (2018).

PubMed PubMed Central Google Scholar

Dhingra, S. K., Small-Saunders, J. L., Ménard, D. & Fidock, D. A. Plasmodium falciparum resistance to piperaquine driven by PfCRT. Lancet Infect. Dis. 19, 1168–1169 (2019).

PubMed PubMed Central Google Scholar

Hamilton, W. L. et al. Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study. Lancet Infect. Dis. 19, 943–951 (2019).

PubMed PubMed Central Google Scholar

Kim, J. et al. Structure and drug resistance of the Plasmodium falciparum transporter PfCRT. Nature 576, 315–320 (2019). The emergence of mutations in the chloroquine resistance transporter resulted in a worldwide crisis and an urgent search for new medicines. Here, the structure of PfCRT isoforms resistant to chloroquine was solved, demonstrating how these mutations confer resistance.

CAS PubMed PubMed Central Google Scholar

Agrawal, S. et al. Association of a novel mutation in the Plasmodium falciparum chloroquine resistance transporter with decreased piperaquine sensitivity. J. Infect. Dis. 216, 468–476 (2017).

CAS PubMed PubMed Central Google Scholar

Small-Saunders, J. L. et al. Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance. PLoS Pathog. 18, e1010278 (2022).

CAS PubMed PubMed Central Google Scholar

van der Pluijm, R. W. et al. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial. Lancet 395, 1345–1360 (2020).

PubMed PubMed Central Google Scholar

van der Pluijm, R. W., Amaratunga, C., Dhorda, M. & Dondorp, A. M. Triple artemisinin-based combination therapies for malaria — a new paradigm? Trends Parasitol. 37, 15–24 (2021).

PubMed Google Scholar

Boni, M. F., White, N. J. & Baird, J. K. The community as the patient in malaria-endemic areas: preempting drug resistance with multiple first-line therapies. PLoS Med. 13, e1001984 (2016).

PubMed PubMed Central Google Scholar

Marwa, K. et al. Therapeutic efficacy of artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine in the treatment of uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa: a systematic review and meta-analysis. PLoS ONE 17, e0264339 (2022).

CAS PubMed PubMed Central Google Scholar

Chotsiri, P. et al. Piperaquine pharmacokinetics during intermittent preventive treatment for malaria in pregnancy. Antimicrob. Agents Chemother. https://doi.org/10.1128/AAC.01150-20 (2021).

Article PubMed PubMed Central Google Scholar

Qiu, D. et al. A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin. Nat. Commun. 13, 5746 (2022).

CAS PubMed PubMed Central Google Scholar

Schmitt, E. K. et al. Efficacy of cipargamin (KAE609) in a randomized, phase II dose-escalation study in adults in sub-Saharan Africa with uncomplicated Plasmodium falciparum malaria. Clin. Infect. Dis. 74, 1831–1839 (2022).

CAS PubMed Google Scholar

Duffey, M. et al. Assessing risks of Plasmodium falciparum resistance to select next-generation antimalarials. Trends Parasitol. 37, 709–721 (2021).

CAS PubMed PubMed Central Google Scholar

Tse, E. G., Korsik, M. & Todd, M. H. The past, present and future of anti-malarial medicines. Malar. J. 18, 93 (2019).

PubMed PubMed Central Google Scholar

Guantai, E. & Chibale, K. How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials? Malar. J. 10, S2 (2011).

CAS PubMed PubMed Central Google Scholar

Plouffe, D. et al. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proc. Natl Acad. Sci. USA 105, 9059–9064 (2008).

CAS PubMed PubMed Central Google Scholar

Guiguemde, W. A. et al. Chemical genetics of Plasmodium falciparum. Nature 465, 311–315 (2010).

CAS PubMed PubMed Central Google Scholar

Miguel-Blanco, C. et al. Hundreds of dual-stage antimalarial molecules discovered by a functional gametocyte screen. Nat. Commun. 8, 15160 (2017).

CAS PubMed PubMed Central Google Scholar

Gamo, F. J. et al. Thousands of chemical starting points for antimalarial lead identification. Nature 465, 305–310 (2010).

CAS PubMed Google Scholar

Hovlid, M. L. & Winzeler, E. A. Phenotypic screens in antimalarial drug discovery. Trends Parasitol. 32, 697–707 (2016).

CAS PubMed PubMed Central Google Scholar

Delves, M. J. et al. A high throughput screen for next-generation leads targeting malaria parasite transmission. Nat. Commun. 9, 3805 (2018).

PubMed PubMed Central Google Scholar

Antonova-Koch, Y. et al. Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. Science https://doi.org/10.1126/science.aat9446 (2018). A significant example of one of the first screening campaigns against the parasite liver stage that revealed novel scaffolds and compounds with previously unidentified mechanisms of action.

Article PubMed PubMed Central Google Scholar

Abraham, M. et al. Probing the open global health chemical diversity library for multistage-active starting points for next-generation antimalarials. ACS Infect. Dis. https://doi.org/10.1021/acsinfecdis.9b00482 (2020).

Article PubMed PubMed Central Google Scholar

Guiguemde, W. A. et al. Global phenotypic screening for antimalarials. Chem. Biol. 19, 116–129 (2012).

CAS PubMed PubMed Central Google Scholar

Xie, S. C. et al. Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2107213118 (2021).

Article PubMed PubMed Central Google Scholar

Favuzza, P. et al. Dual plasmepsin-targeting antimalarial agents disrupt multiple stages of the malaria parasite life cycle. Cell Host Microbe 27, 642–658 (2020).

CAS PubMed PubMed Central Google Scholar

Forte, B. et al. Prioritization of molecular targets for antimalarial drug discovery. ACS Infect. Dis. 7, 2764–2776 (2021). Describes the most important criteria for selecting targets for antimalarial drug discovery and analyses several drug targets in the MalDA pipeline as well as strategies for identifying additional drug targets.

CAS PubMed PubMed Central Google Scholar

Chughlay, M. F. et al. Chemoprotective antimalarial activity of P218 against Plasmodium falciparum: a randomized, placebo-controlled volunteer infection study. Am. J. Trop. Med. Hyg. 104, 1348–1358 (2021).

CAS PubMed PubMed Central Google Scholar

Baldwin, J. et al. High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J. Biol. Chem. 280, 21847–21853 (2005).

CAS PubMed Google Scholar

Phillips, M. A. et al. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Sci. Transl Med. 7, 296ra111 (2015).

PubMed PubMed Central Google Scholar

Llanos-Cuentas, A. et al. Antimalarial activity of single-dose DSM265, a novel Plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study. Lancet Infect. Dis. 18, 874–883 (2018).

CAS PubMed PubMed Central Google Scholar

Agarwal, A. et al. Discovery of a selective, safe and novel anti-malarial compound with activity against chloroquine resistant strain of Plasmodium falciparum. Sci. Rep. 5, 13838 (2015).

PubMed PubMed Central Google Scholar

Pavadai, E. et al. Identification of new human malaria parasite Plasmodium falciparum dihydroorotate dehydrogenase inhibitors by pharmacophore and structure-based virtual screening. J. Chem. Inf. Model. 56, 548–562 (2016).

CAS PubMed PubMed Central Google Scholar

Uddin, A. et al. Target-based virtual screening of natural compounds identifies a potent antimalarial with selective falcipain-2 inhibitory activity. Front. Pharmacol. 13, 850176 (2022).

CAS PubMed PubMed Central Google Scholar

Dascombe, M. J. et al. Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine. J. Med. Chem. 48, 5423–5436 (2005).

CAS PubMed Google Scholar

de Sousa, A. C. C., Combrinck, J. M., Maepa, K. & Egan, T. J. Virtual screening as a tool to discover new beta-haematin inhibitors with activity against malaria parasites. Sci. Rep. 10, 3374 (2020).

PubMed PubMed Central Google Scholar

Ruggeri, C. et al. Identification and validation of a potent dual inhibitor of the P. falciparum M1 and M17 aminopeptidases using virtual screening. PLoS ONE 10, e0138957 (2015).

PubMed PubMed Central Google Scholar

Godinez, W. J. et al. Design of potent antimalarials with generative chemistry. Nat. Mach. Intell. 4, 180–186 (2022).

Google Scholar

Yang, T. et al. MalDA, accelerating malaria drug discovery. Trends Parasitol. 37, 493–507 (2021).

CAS PubMed PubMed Central Google Scholar

Summers, R. L. et al. Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention. Cell Chem. Biol. 29, 191–201 (2022). Reports P. falciparum acetyl-coenzyme A synthase as an essential protein for parasite viability associated with histone acetylation and shows it can be inhibited by small molecules (MMV019721 and MMV084978).

CAS PubMed PubMed Central Google Scholar

Schalkwijk, J. et al. Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum. Sci. Transl Med. 11, eaas9917 (2019).

CAS PubMed Google Scholar

Paquet, T. et al. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci. Transl Med. 9, eaad9735 (2017). Describes the development of MMV390048, the first candidate drug discovered and developed entirely in Africa, the first antimalarial kinase inhibitor tested in humans, and the first antimalarial with a phase I trial performed in Africa.

PubMed PubMed Central Google Scholar

Vanaerschot, M. et al. Inhibition of resistance-refractory P. falciparum kinase PKG delivers prophylactic, blood stage, and transmission-blocking antiplasmodial activity. Cell Chem. Biol. 27, 806–816.e8 (2020).

CAS PubMed PubMed Central Google Scholar

Dziekan, J. M. et al. Cellular thermal shift assay for the identification of drug-target interactions in the Plasmodium falciparum proteome. Nat. Protoc. 15, 1881–1921 (2020).

CAS PubMed Google Scholar

Begolo, D., Erben, E. & Clayton, C. Drug target identification using a trypanosome overexpression library. Antimicrob. Agents Chemother. 58, 6260–6264 (2014).

PubMed PubMed Central Google Scholar

Melief, E. et al. Construction of an overexpression library for Mycobacterium tuberculosis. Biol. Methods Protoc. 3, bpy009 (2018).

PubMed PubMed Central Google Scholar

Allman, E. L., Painter, H. J., Samra, J., Carrasquilla, M. & Llinás, M. Metabolomic profiling of the malaria box reveals antimalarial target pathways. Antimicrob. Agents Chemother. 60, 6635–6649 (2016).

CAS PubMed PubMed Central Google Scholar

Ganesan, S. M., Falla, A., Goldfless, S. J., Nasamu, A. S. & Niles, J. C. Synthetic RNA-protein modules integrated with native translation mechanisms to control gene expression in malaria parasites. Nat. Commun. 7, 10727 (2016).

CAS PubMed PubMed Central Google Scholar

Hoepfner, D. et al. Selective and specific inhibition of the Plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin. Cell Host Microbe 11, 654–663 (2012).

CAS PubMed PubMed Central Google Scholar

Baragana, B. et al. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proc. Natl Acad. Sci. USA 116, 7015–7020 (2019).

PubMed PubMed Central Google Scholar

Kato, N. et al. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 538, 344–349 (2016).

CAS PubMed PubMed Central Google Scholar

Tye, M. A. et al. Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone-resistance. Nat. Commun. 13, 4976 (2022). Reports the development of an aminoacyl tRNA synthetase biochemical assay based on TR-FRET and the design of P. falciparum prolyl-tRNA synthetase high-affinity inhibitors that can simultaneously engage all three substrate-binding pockets of the enzyme.

CAS PubMed PubMed Central Google Scholar

Sonoiki, E. et al. Antimalarial benzoxaboroles target Plasmodium falciparum Leucyl-tRNA synthetase. Antimicrob. Agents Chemother. 60, 4886–4895 (2016).

CAS PubMed PubMed Central Google Scholar

Xie, S. C. et al. Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy. Science 376, 1074–1079 (2022). Reports a novel biochemical feature of P. falciparum aminoacyl tRNA synthetases and identifies and characterizes a potent inhibitor with activity across the parasite lifecycle that acts via reaction hijacking.

CAS PubMed PubMed Central Google Scholar

Istvan, E. S. et al. Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target. Sci. Transl Med. 15, eadc9249 (2023).

CAS PubMed Google Scholar

Sharma, M. et al. Structural basis of malaria parasite phenylalanine tRNA-synthetase inhibition by bicyclic azetidines. Nat. Commun. 12, 343 (2021).

CAS PubMed PubMed Central Google Scholar

Jain, V. et al. Structure of prolyl-tRNA synthetase-halofuginone complex provides basis for development of drugs against malaria and toxoplasmosis. Structure 23, 819–829 (2015).

CAS PubMed Google Scholar

Ndagi, U., Kumalo, H. M. & Mhlongo, N. N. A consequence of drug targeting of aminoacyl-tRNA synthetases in Mycobacterium tuberculosis. Chem. Biol. Drug Des. 98, 421–434 (2021).

CAS PubMed Google Scholar

Jain, V. et al. Targeting prolyl-tRNA synthetase to accelerate drug discovery against malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis, and coccidiosis. Structure 25, 1495–1505.e6 (2017).

CAS PubMed Google Scholar

Tandon, S. et al. Deciphering the interaction of benzoxaborole inhibitor AN2690 with connective polypeptide 1 (CP1) editing domain of Leishmania donovani leucyl-tRNA synthetase. J. Biosci. 45, 63 (2020).

CAS PubMed Google Scholar

Mishra, S. et al. Conformational heterogeneity in apo and drug-bound structures of Toxoplasma gondii prolyl-tRNA synthetase. Acta Crystallogr. F. Struct. Biol. Commun. 75, 714–724 (2019).

CAS PubMed PubMed Central Google Scholar

Radke, J. B. et al. Bicyclic azetidines target acute and chronic stages of Toxoplasma gondii by inhibiting parasite phenylalanyl t-RNA synthetase. Nat. Commun. 13, 459 (2022).

CAS PubMed PubMed Central Google Scholar

Alam, M. M. et al. Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target. Science https://doi.org/10.1126/science.aau1682 (2019).

Article PubMed PubMed Central Google Scholar

Ducati, R. G. et al. Genetic resistance to purine nucleoside phosphorylase inhibition in Plasmodium falciparum. Proc. Natl Acad. Sci. USA 115, 2114–2119 (2018).

CAS PubMed PubMed Central Google Scholar

Xie, S. C. et al. Target validation and identification of novel boronate inhibitors of the Plasmodium falciparum proteasome. J. Med. Chem. 61, 10053–10066 (2018).

CAS PubMed PubMed Central Google Scholar

Stokes, B. H. et al. Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents. PLoS Pathog. 15, e1007722 (2019).

CAS PubMed PubMed Central Google Scholar

Zhan, W. et al. Development of a highly selective Plasmodium falciparum proteasome inhibitor with anti-malaria activity in humanized mice. Angew. Chem. Int. Ed. Engl. 60, 9279–9283 (2021).

CAS PubMed PubMed Central Google Scholar

LaMonte, G. M. et al. Development of a potent inhibitor of the Plasmodium proteasome with reduced mammalian toxicity. J. Med. Chem. 60, 6721–6732 (2017).

CAS PubMed PubMed Central Google Scholar

Li, H. et al. Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature 530, 233–236 (2016).

CAS PubMed PubMed Central Google Scholar

Yoo, E. et al. Defining the determinants of specificity of Plasmodium proteasome inhibitors. J. Am. Chem. Soc. 140, 11424–11437 (2018).

CAS PubMed PubMed Central Google Scholar

Deni, I. et al. Mitigating the risk of antimalarial resistance via covalent dual-subunit inhibition of the Plasmodium proteasome. Cell Chem. Biol. 30, 470–485 (2023).

CAS PubMed PubMed Central Google Scholar

Wyllie, S. et al. Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition. Proc. Natl Acad. Sci. USA 116, 9318–9323 (2019).

CAS PubMed PubMed Central Google Scholar

Khare, S. et al. Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature 537, 229–233 (2016).

CAS PubMed PubMed Central Google Scholar

Lima, M. L. et al. Identification of a proteasome-targeting arylsulfonamide with potential for the treatment of Chagas’ disease. Antimicrob. Agents Chemother. 66, e0153521 (2022).

PubMed Google Scholar

Waller, R. F. et al. A type II pathway for fatty acid biosynthesis presents drug targets in Plasmodium falciparum. Antimicrob. Agents Chemother. 47, 297–301 (2003).

CAS PubMed PubMed Central Google Scholar

Yeh, E. & DeRisi, J. L. Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum. PLoS Biol. 9, e1001138 (2011).

CAS PubMed PubMed Central Google Scholar

Kennedy, K., Crisafulli, E. M. & Ralph, S. A. Delayed death by plastid inhibition in apicomplexan parasites. Trends Parasitol. 35, 747–759 (2019).

CAS PubMed Google Scholar

Tang, Y. et al. A mutagenesis screen for essential plastid biogenesis genes in human malaria parasites. PLoS Biol. 17, e3000136 (2019).

PubMed PubMed Central Google Scholar

Zhang, M. et al. Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis. Science https://doi.org/10.1126/science.aap7847 (2018).

Article PubMed PubMed Central Google Scholar

Bushell, E. et al. Functional profiling of a Plasmodium genome reveals an abundance of essential genes. Cell 170, 260–272.e8 (2017).

CAS PubMed PubMed Central Google Scholar

Stanway, R. R. et al. Genome-scale identification of essential metabolic processes for targeting the Plasmodium liver stage. Cell 179, 1112–1128 (2019).

CAS PubMed PubMed Central Google Scholar

MMV. MMV’s Pipeline of Antimalarial Drugs https://www.mmv.org/research-development/mmvs-pipeline-antimalarial-drugs (2023).

Abd-Rahman, A. N., Zaloumis, S., McCarthy, J. S., Simpson, J. A. & Commons, R. J. Scoping review of antimalarial drug candidates in phase I and II drug development. Antimicrob. Agents Chemother. 66, e0165921 (2022).

PubMed Google Scholar

Wu, R. L. et al. Low-dose subcutaneous or intravenous monoclonal antibody to prevent malaria. N. Engl. J. Med. 387, 397–407 (2022).

CAS PubMed PubMed Central Google Scholar

Hameed, P. S. et al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat. Commun. 6, 6715 (2015).

Google Scholar

Barber, B. E. et al. Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study. Lancet Infect. Dis. 22, 879–890 (2022).

CAS PubMed Google Scholar

Daubenberger, C. & Burrows, J. N. Volunteer infection studies accelerate the clinical development of novel drugs against malaria. Lancet Infect. Dis. 22, 753–754 (2022).

CAS PubMed Google Scholar

Dive, D. & Biot, C. Ferroquine as an oxidative shock antimalarial. Curr. Top. Med. Chem. 14, 1684–1692 (2014).

CAS PubMed Google Scholar

Baragana, B. et al. A novel multiple-stage antimalarial agent that inhibits protein synthesis. Nature 522, 315–320 (2015).

CAS PubMed PubMed Central Google Scholar

Baragana, B. et al. Discovery of a quinoline-4-carboxamide derivative with a novel mechanism of action, multistage antimalarial activity, and potent in vivo efficacy. J. Med. Chem. 59, 9672–9685 (2016).

CAS PubMed PubMed Central Google Scholar

Rottmann, M. et al. Preclinical antimalarial combination study of M5717, a Plasmodium falciparum elongation factor 2 inhibitor, and pyronaridine, a hemozoin formation inhibitor. Antimicrob. Agents Chemother. https://doi.org/10.1128/AAC.02181-19 (2020).

Article PubMed PubMed Central Google Scholar

McCarthy, J. S. et al. Safety, pharmacokinetics, and antimalarial activity of the novel Plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study. Lancet Infect. Dis. 21, 1713–1724 (2021). Reports promising human efficacy data with M5717 (cabamiquine) that is the basis of a phase II trial combination with pyronaridine.

CAS PubMed PubMed Central Google Scholar

Meister, S. et al. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334, 1372–1377 (2011).

CAS PubMed PubMed Central Google Scholar

Kuhen, K. L. et al. KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission. Antimicrob. Agents Chemother. 58, 5060–5067 (2014).

PubMed PubMed Central Google Scholar

Lehane, A. M. et al. Characterization of the ATP4 ion pump in Toxoplasma gondii. J. Biol. Chem. 294, 5720–5734 (2019).

CAS PubMed PubMed Central Google Scholar

Kreutzfeld, O. et al. Associations between varied susceptibilities of PfATP4 inhibitors and genotypes in Ugandan Plasmodium falciparum isolates. Antimicrob. Agents Chemother. https://doi.org/10.1128/aac.00771-21 (2021).

Article PubMed PubMed Central Google Scholar

Flannery, E. L. et al. Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials. ACS Chem. Biol. 10, 413–420 (2015).

CAS PubMed Google Scholar

Lim, M. Y. et al. UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes. Nat. Microbiol. 1, 16166 (2016).

CAS PubMed PubMed Central Google Scholar

LaMonte, G. et al. Mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) confer multidrug resistance. mBio https://doi.org/10.1128/mBio.00696-16 (2016).

Article PubMed PubMed Central Google Scholar

Magistrado, P. A. et al. Plasmodium falciparum cyclic amine resistance locus (PfCARL), a resistance mechanism for two distinct compound classes. ACS Infect. Dis. 2, 816–826 (2016).

CAS PubMed PubMed Central Google Scholar

Kublin, J. G. et al. Safety, pharmacokinetics, and causal prophylactic efficacy of KAF156 in a Plasmodium falciparum human infection study. Clin. Infect. Dis. 73, e2407–e2414 (2021).

CAS PubMed Google Scholar

Shah, R. et al. Formulation development and characterization of lumefantrine nanosuspension for enhanced antimalarial activity. J. Biomater. Sci. Polym. Ed. 32, 833–857 (2021).

CAS PubMed Google Scholar

NOVARTIS. Novartis and Medicines for Malaria Venture Announce Decision to move to Phase 3 study for Novel Ganaplacide/Lumefantrine-SDF Combination in Adults and Children with Malaria https://www.novartis.com/news/media-releases/novartis-and-medicines-malaria-venture-announce-decision-move-phase-3-study-novel-ganaplacidelumefantrine-sdf-combination-adults-and-children-malaria (2022).

Srivastava, I. K. & Vaidya, A. B. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob. Agents Chemother. 43, 1334–1339 (1999).

CAS PubMed PubMed Central Google Scholar

Murithi, J. M. et al. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance. Sci. Transl Med https://doi.org/10.1126/scitranslmed.abg6013 (2021). Reports a promising new antimalarial with a low resistance risk, fast parasite clerance and excellent pharmacological properties.

Article PubMed PubMed Central Google Scholar

Taft, B. R. et al. Discovery and preclinical pharmacology of INE963, a potent and fast-acting blood-stage antimalarial with a high barrier to resistance and potential for single-dose cures in uncomplicated malaria. J. Med. Chem. 65, 3798–3813 (2022). INE963 is a novel irresistible chemotype with fast parasite clearance and is completing phase I clinical study.

CAS PubMed PubMed Central Google Scholar

Duffy, P. E. & Patrick Gorres, J. Malaria vaccines since 2000: progress, priorities, products. NPJ Vaccines 5, 48 (2020).

PubMed PubMed Central Google Scholar

Pethrak, C. et al. New Insights into antimalarial chemopreventive activity of antifolates. Antimicrob. Agents Chemother. 66, e0153821 (2022).

PubMed Google Scholar

Katsuno, K. et al. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discov. 14, 751–758 (2015).

CAS PubMed Google Scholar

de Vries, L. E. et al. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183. Nat. Commun. 13, 2158 (2022).

PubMed PubMed Central Google Scholar

Pegoraro, S. et al. SC83288 is a clinical development candidate for the treatment of severe malaria. Nat. Commun. 8, 14193 (2017).

CAS PubMed PubMed Central Google Scholar

MMV. MMV’s Pipeline of Antimalarial Drugs: GSK484 https://www.mmv.org/mmv-pipeline-antimalarial-drugs/gsk484 (2023).

MMV. MMV’s Pipeline of Antimalarial Drugs: IWY35 https://www.mmv.org/mmv-pipeline-antimalarial-drugs/iwy357 (2023).

Tisnerat, C., Dassonville-Klimpt, A., Gosselet, F. & Sonnet, P. Antimalarial drug discovery: from quinine to the most recent promising clinical drug candidates. Curr. Med. Chem. 29, 3326–3365 (2022).

CAS PubMed Google Scholar

Smilkstein, M. J. et al. ELQ-331 as a prototype for extremely durable chemoprotection against malaria. Malar. J. 18, 291 (2019).

PubMed PubMed Central Google Scholar

Nilsen, A. et al. Quinolone-3-diarylethers: a new class of antimalarial drug. Sci. Transl Med. 5, 177ra137 (2013).

Google Scholar

Dola, V. R. et al. Synthesis and evaluation of chirally defined side chain variants of 7-chloro-4-aminoquinoline to overcome drug resistance in malaria chemotherapy.Antimicrob. Agents Chemother. 61, e01152-16 (2017).

PubMed PubMed Central Google Scholar

MMV. MMV’s Pipeline of Antimalarial Drugs: MMV609 https://www.mmv.org/mmv-pipeline-antimalarial-drugs/mmv609 (2023).

Jimenez-Diaz, M. B. et al. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc. Natl Acad. Sci. USA 111, E5455–E5462 (2014).

CAS PubMed PubMed Central Google Scholar

Sulyok, M. et al. DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection. Lancet Infect. Dis. 17, 636–644 (2017).

CAS PubMed PubMed Central Google Scholar

Demarta-Gatsi, C. et al. Malarial PI4K inhibitor induced diaphragmatic hernias in rat: potential link with mammalian kinase inhibition. Birth Defects Res. 114, 487–498 (2022).

CAS PubMed PubMed Central Google Scholar

Moehrle, J. J. et al. First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. Br. J. Clin. Pharmacol. 75, 524–537 (2013).

CAS PubMed Google Scholar

Adoke, Y. et al. A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria. Malar. J. 20, 222 (2021).

CAS PubMed PubMed Central Google Scholar

Ravikumar, A., Arzumanyan, G. A., Obadi, M. K. A., Javanpour, A. A. & Liu, C. C. Scalable, continuous evolution of genes at mutation rates above genomic error thresholds. Cell 175, 1946–1957 (2018).

CAS PubMed PubMed Central Google Scholar

Christopoulos, K. A. et al. First demonstration project of long-acting injectable antiretroviral therapy for persons with and without detectable HIV viremia in an urban HIV clinic. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciac631 (2022).

Article PubMed PubMed Central Google Scholar

Schmidt, H. A., Rodolph, M., Schaefer, R., Baggaley, R. & Doherty, M. Long-acting injectable cabotegravir: implementation science needed to advance this additional HIV prevention choice. J. Int. AIDS Soc. 25, e25963 (2022).

CAS PubMed PubMed Central Google Scholar

Song, Z., Iorga, B. I., Mounkoro, P., Fisher, N. & Meunier, B. The antimalarial compound ELQ-400 is an unusual inhibitor of the bc1 complex, targeting both Qo and Qi sites. FEBS Lett. 592, 1346–1356 (2018).

CAS PubMed Google Scholar

Stickles, A. M. et al. Atovaquone and ELQ-300 combination therapy as a novel dual-site cytochrome bc1 inhibition strategy for malaria. Antimicrob. Agents Chemother. 60, 4853–4859 (2016).

CAS PubMed PubMed Central Google Scholar

de Villiers, K. A. & Egan, T. J. Heme detoxification in the malaria parasite: a target for antimalarial drug development. Acc. Chem. Res. 54, 2649–2659 (2021).

PubMed PubMed Central Google Scholar

Heinberg, A. & Kirkman, L. The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations. Ann. NY Acad. Sci. 1342, 10–18 (2015).

CAS PubMed Google Scholar

Chitnumsub, P. et al. The structure of Plasmodium falciparum hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase reveals the basis of sulfa resistance. FEBS J. 287, 3273–3297 (2020).

CAS PubMed Google Scholar

Wang, X. et al. MEPicides: α,β-unsaturated fosmidomycin analogues as DXR inhibitors against malaria. J. Med. Chem. 61, 8847–8858 (2018).

CAS PubMed PubMed Central Google Scholar

Herman, J. D. et al. The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Sci. Transl Med. 7, 288ra277 (2015).

Google Scholar

Keller, T. L. et al. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat. Chem. Biol. 8, 311–317 (2012).

CAS PubMed PubMed Central Google Scholar

Derbyshire, E. R., Mazitschek, R. & Clardy, J. Characterization of Plasmodium liver stage inhibition by halofuginone. ChemMedChem 7, 844–849 (2012).

CAS PubMed PubMed Central Google Scholar

Dharia, N. V. et al. Genome scanning of Amazonian Plasmodium falciparum shows subtelomeric instability and clindamycin-resistant parasites. Genome Res. 20, 1534–1544 (2010).

CAS PubMed PubMed Central Google Scholar

Collins, K. A. et al. DSM265 at 400 milligrams clears asexual stage parasites but not mature gametocytes from the blood of healthy subjects experimentally infected with Plasmodium falciparum. Antimicrob. Agents Chemother. https://doi.org/10.1128/AAC.01837-18 (2019).

Article PubMed PubMed Central Google Scholar

White, J. et al. Identification and mechanistic understanding of dihydroorotate dehydrogenase point mutations in Plasmodium falciparum that confer in vitro resistance to the clinical candidate DSM265. ACS Infect. Dis. 5, 90–101 (2019).

CAS PubMed Google Scholar

Belard, S. & Ramharter, M. DSM265: a novel drug for single-dose cure of Plasmodium falciparum malaria. Lancet Infect. Dis. 18, 819–820 (2018).

PubMed Google Scholar

Palmer, M. J. et al. Potent antimalarials with development potential identified by structure-guided computational optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series. J. Med. Chem. 64, 6085–6136 (2021).

CAS PubMed PubMed Central Google Scholar

Ndayisaba, G. et al. Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa. Malar. J. 20, 478 (2021).

CAS PubMed PubMed Central Google Scholar

McCarthy, J. S. et al. Defining the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum. Antimicrob. Agents Chemother. https://doi.org/10.1128/AAC.01423-20 (2021).

Article PubMed PubMed Central Google Scholar

Ashton, T. D. et al. Optimization of 2,3-dihydroquinazolinone-3-carboxamides as antimalarials targeting PfATP4. J. Med. Chem. https://doi.org/10.1021/acs.jmedchem.2c02092 (2023).

Article PubMed PubMed Central Google Scholar

Liang, X. et al. Discovery of 6′-chloro-N-methyl-5′-(phenylsulfonamido)-[3,3′-bipyridine]−5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium. Eur. J. Med. Chem. 188, 112012 (2020).

CAS PubMed Google Scholar

Brunschwig, C. et al. UCT943, a next-generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria.Antimicrob. Agents Chemother. 62, e00012-18 (2018).

PubMed PubMed Central Google Scholar

Cabrera, D. G. et al. Plasmodial kinase inhibitors: license to cure? J. Med. Chem. 61, 8061–8077 (2018).

CAS PubMed PubMed Central Google Scholar

Sinxadi, P. et al. Safety, tolerability, pharmacokinetics, and antimalarial activity of the novel Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048 in healthy volunteers. Antimicrob. Agents Chemother. https://doi.org/10.1128/aac.01896-19 (2020).

Article PubMed PubMed Central Google Scholar

Khandelwal, A. et al. Translation of liver stage activity of M5717, a Plasmodium elongation factor 2 inhibitor: from bench to bedside. Malar. J. 21, 151 (2022).

CAS PubMed PubMed Central Google Scholar

Ng, C. L. et al. CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs. Mol. Microbiol. 101, 381–393 (2016).

CAS PubMed PubMed Central Google Scholar

de Lera Ruiz, M. et al. The invention of WM382, a highly potent PMIX/X dual inhibitor toward the treatment of malaria. ACS Med. Chem. Lett. 13, 1745–1754 (2022).

PubMed Google Scholar

Lowe, M. A. et al. Discovery and characterization of potent, efficacious, orally available antimalarial plasmepsin X inhibitors and preclinical safety assessment of UCB7362. J. Med. Chem. 65, 14121–14143 (2022).

CAS PubMed PubMed Central Google Scholar

Nasamu, A. S. et al. Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion. Science 358, 518–522 (2017).

CAS PubMed PubMed Central Google Scholar

Schwertz, G. et al. Antimalarial inhibitors targeting serine hydroxymethyltransferase (SHMT) with in vivo efficacy and analysis of their binding mode based on X-ray cocrystal structures. J. Med. Chem. 60, 4840–4860 (2017).

CAS PubMed Google Scholar

Zaki, M. E. A., Al-Hussain, S. A., Masand, V. H., Akasapu, S. & Lewaa, I. QSAR and pharmacophore modeling of nitrogen heterocycles as potent human N-myristoyltransferase (Hs-NMT) inhibitors. Molecules https://doi.org/10.3390/molecules26071834 (2021).

Article PubMed PubMed Central Google Scholar

Schlott, A. C., Holder, A. A. & Tate, E. W. N-Myristoylation as a drug target in malaria: exploring the role of N-myristoyltransferase substrates in the inhibitor mode of action. ACS Infect. Dis. 4, 449–457 (2018).

CAS PubMed Google Scholar

de Vries, L. E., Lunghi, M., Krishnan, A., Kooij, T. W. A. & Soldati-Favre, D. Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets. PLoS Pathog. 17, e1010124 (2021).

PubMed PubMed Central Google Scholar

Bopp, S. et al. Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation. Nat. Commun. 14, 1455 (2023).

CAS PubMed PubMed Central Google Scholar

Chhibber-Goel, J., Yogavel, M. & Sharma, A. Structural analyses of the malaria parasite aminoacyl-tRNA synthetases provide new avenues for antimalarial drug discovery. Protein Sci. 30, 1793–1803 (2021).

CAS PubMed PubMed Central Google Scholar

Novoa, E. M. et al. Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo. Proc. Natl Acad. Sci. USA 111, E5508–E5517 (2014).

CAS PubMed PubMed Central Google Scholar

von Bredow, L. et al. Synthesis, antiplasmodial, and antileukemia activity of dihydroartemisinin-HDAC inhibitor hybrids as multitarget drugs. Pharmaceuticals https://doi.org/10.3390/ph15030333 (2022).

Article Google Scholar

Jublot, D. et al. A histone deacetylase (HDAC) inhibitor with pleiotropic in vitro anti-toxoplasma and anti-Plasmodium activities controls acute and chronic toxoplasma infection in mice. Int. J. Mol. Sci. https://doi.org/10.3390/ijms23063254 (2022).

Article PubMed PubMed Central Google Scholar

Wang, M. et al. Drug repurposing of quisinostat to discover novel Plasmodium falciparum HDAC1 inhibitors with enhanced triple-stage antimalarial activity and improved safety. J. Med. Chem. 65, 4156–4181 (2022).

CAS PubMed Google Scholar

Zhang, H. et al. Design, synthesis, and optimization of macrocyclic peptides as species-selective antimalaria proteasome inhibitors. J. Med. Chem. 65, 9350–9375 (2022).

CAS PubMed PubMed Central Google Scholar

Almaliti, J. et al. Development of potent and highly selective epoxyketone-based Plasmodium proteasome inhibitors. Chemistry https://doi.org/10.1002/chem.202203958 (2023).

Article PubMed Google Scholar

Kabeche, S. et al. Nonbisphosphonate inhibitors of Plasmodium falciparum FPPS/GGPPS. Bioorg Med. Chem. Lett. 41, 127978 (2021).

CAS PubMed Google Scholar

Gisselberg, J. E., Herrera, Z., Orchard, L. M., Llinás, M. & Yeh, E. Specific inhibition of the bifunctional farnesyl/geranylgeranyl diphosphate synthase in malaria parasites via a new small-molecule binding site. Cell Chem. Biol. 25, 185–193.e5 (2018).

CAS PubMed Google Scholar

Venkatramani, A., Gravina Ricci, C., Oldfield, E. & McCammon, J. A. Remarkable similarity in Plasmodium falciparum and Plasmodium vivax geranylgeranyl diphosphate synthase dynamics and its implication for antimalarial drug design. Chem. Biol. Drug Des. 91, 1068–1077 (2018).

CAS PubMed PubMed Central Google Scholar

Gabriel, H. B. et al. Single-target high-throughput transcription analyses reveal high levels of alternative splicing present in the FPPS/GGPPS from Plasmodium falciparum. Sci. Rep. 5, 18429 (2015).

CAS PubMed PubMed Central Google Scholar

Jordão, F. M. et al. Cloning and characterization of bifunctional enzyme farnesyl diphosphate/geranylgeranyl diphosphate synthase from Plasmodium falciparum. Malar. J. 12, 184 (2013).

PubMed PubMed Central Google Scholar

Ricci, C. G. et al. Dynamic structure and inhibition of a malaria drug target: geranylgeranyl diphosphate synthase. Biochemistry 55, 5180–5190 (2016).

Google Scholar

Istvan, E. S. et al. Plasmodium Niemann-Pick type C1-related protein is a druggable target required for parasite membrane homeostasis. eLife https://doi.org/10.7554/eLife.40529 (2019).

Article PubMed PubMed Central Google Scholar

Moustakim, M. et al. Discovery of a PCAF bromodomain chemical probe. Angew. Chem. Int. Ed. Engl. 56, 827–831 (2017).

CAS PubMed Google Scholar

Swift, R. P., Rajaram, K., Liu, H. B. & Prigge, S. T. Dephospho-CoA kinase, a nuclear-encoded apicoplast protein, remains active and essential after Plasmodium falciparum apicoplast disruption. EMBO J. 40, e107247 (2021).

CAS PubMed PubMed Central Google Scholar

Fletcher, S. et al. Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway. Parasit. Vectors 9, 589 (2016).

PubMed PubMed Central Google Scholar

Salazar, E. et al. Characterization of Plasmodium falciparum adenylyl cyclase-β and its role in erythrocytic stage parasites. PLoS ONE 7, e39769 (2012).

CAS PubMed PubMed Central Google Scholar

Jiang, X. An overview of the Plasmodium falciparum hexose transporter and its therapeutic interventions. Proteins https://doi.org/10.1002/prot.26351 (2022).

Article PubMed PubMed Central Google Scholar

Barbieri, D. et al. The phosphodiesterase inhibitor tadalafil promotes splenic retention of Plasmodium falciparum gametocytes in humanized mice. Front. Cell Infect. Microbiol. 12, 883759 (2022).

CAS PubMed PubMed Central Google Scholar

Ding, S. et al. Probing the B- & C-rings of the antimalarial tetrahydro-beta-carboline MMV008138 for steric and conformational constraints. Bioorg Med. Chem. Lett. 30, 127520 (2020).

CAS PubMed PubMed Central Google Scholar

Imlay, L. S. et al. Plasmodium IspD (2-C-methyl-D-erythritol 4-phosphate cytidyltransferase), an essential and druggable antimalarial target. ACS Infect. Dis. 1, 157–167 (2015).

CAS PubMed PubMed Central Google Scholar

Nerlich, C., Epalle, N. H., Seick, P. & Beitz, E. Discovery and development of inhibitors of the plasmodial FNT-type lactate transporter as novel antimalarials. Pharmaceuticals https://doi.org/10.3390/ph14111191 (2021).

Article PubMed PubMed Central Google Scholar

Walloch, P., Hansen, C., Priegann, T., Schade, D. & Beitz, E. Pentafluoro-3-hydroxy-pent-2-en-1-ones potently inhibit FNT-type lactate transporters from all five human-pathogenic Plasmodium species. ChemMedChem 16, 1283–1289 (2021).

CAS PubMed PubMed Central Google Scholar

Peng, X. et al. Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism. PLoS Biol. 19, e3001386 (2021).

CAS PubMed PubMed Central Google Scholar

Hapuarachchi, S. V. et al. The malaria parasite’s lactate transporter PfFNT is the target of antiplasmodial compounds identified in whole cell phenotypic screens. PLoS Pathog. 13, e1006180 (2017).

PubMed PubMed Central Google Scholar

Golldack, A. et al. Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale. PLoS Pathog. 13, e1006172 (2017).

PubMed PubMed Central Google Scholar

Frydrych, J. et al. Nucleotide analogues containing a pyrrolidine, piperidine or piperazine ring: Synthesis and evaluation of inhibition of plasmodial and human 6-oxopurine phosphoribosyltransferases and in vitro antimalarial activity. Eur. J. Med. Chem. 219, 113416 (2021).

CAS PubMed Google Scholar

Wang, X. et al. Identification of Plasmodium falciparum mitochondrial malate: quinone oxidoreductase inhibitors from the pathogen box. Genes https://doi.org/10.3390/genes10060471 (2019).

Article PubMed PubMed Central Google Scholar

Sonoiki, E. et al. A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue. Nat. Commun. 8, 14574 (2017).

PubMed PubMed Central Google Scholar

Yoo, E. et al. The antimalarial natural product salinipostin A identifies essential alpha/beta serine hydrolases involved in lipid metabolism in P. falciparum parasites. Cell Chem. Biol. 27, 143–157 (2020).

CAS PubMed PubMed Central Google Scholar

Burrows, J. N. et al. New developments in anti-malarial target candidate and product profiles. Malar. J. 16, 26 (2017).

PubMed PubMed Central Google Scholar

Wouters, O. J., McKee, M. & Luyten, J. Estimated research and development investment needed to bring a new medicine to market, 2009-2018. J. Am. Med. Assoc. 323, 844–853 (2020).

Google Scholar

Baird, J. K. 8-Aminoquinoline therapy for latent malaria. Clin. Microbiol. Rev. https://doi.org/10.1128/CMR.00011-19 (2019).

Article PubMed PubMed Central Google Scholar

MMV. Keeping the Promise https://www.mmv.org/sites/default/files/uploads/docs/publications/KeepingThePromise-Report_2021.pdf (2021).

de Jong, R. M. et al. Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes. NPJ Vaccines 6, 101 (2021).

PubMed PubMed Central Google Scholar

Rathore, D., Sacci, J. B., de la Vega, P. & McCutchan, T. F. Binding and invasion of liver cells by Plasmodium falciparum sporozoites. Essential involvement of the amino terminus of circumsporozoite protein. J. Biol. Chem. 277, 7092–7098 (2002).

CAS PubMed Google Scholar

Casares, S., Brumeanu, T. D. & Richie, T. L. The RTS,S malaria vaccine. Vaccine 28, 4880–4894 (2010).

CAS PubMed Google Scholar

Gaudinski, M. R. et al. A monoclonal antibody for malaria prevention. N. Engl. J. Med. 385, 803–814 (2021).

CAS PubMed PubMed Central Google Scholar

Kayentao, K. et al. Safety and efficacy of a monoclonal antibody against malaria in Mali. N. Engl. J. Med. 387, 1833–1842 (2022).

CAS PubMed PubMed Central Google Scholar

Wang, L. T. et al. A potent anti-malarial human monoclonal antibody targets circumsporozoite protein minor repeats and neutralizes sporozoites in the liver. Immunity 53, 733–744 (2020).

CAS PubMed PubMed Central Google Scholar

van der Boor, S. C. et al. Safety, tolerability, and Plasmodium falciparum transmission-reducing activity of monoclonal antibody TB31F: a single-centre, open-label, first-in-human, dose-escalation, phase 1 trial in healthy malaria-naive adults. Lancet Infect. Dis. 22, 1596–1605 (2022).

PubMed PubMed Central Google Scholar

Hernandez, I. et al. Pricing of monoclonal antibody therapies: higher if used for cancer? Am. J. Manag. Care 24, 109–112 (2018).

PubMed Google Scholar

Mathews, E. S. & Odom John, A. R. Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination. F1000Res https://doi.org/10.12688/f1000research.14874.1 (2018).

Article PubMed PubMed Central Google Scholar

Macintyre, F. et al. Injectable anti-malarials revisited: discovery and development of new agents to protect against malaria. Malar. J. 17, 402 (2018).

CAS PubMed PubMed Central Google Scholar

Bakshi, R. P. et al. Long-acting injectable atovaquone nanomedicines for malaria prophylaxis. Nat. Commun. 9, 315 (2018).

PubMed PubMed Central Google Scholar

Menze, B. D. et al. Marked aggravation of pyrethroid resistance in major malaria vectors in Malawi between 2014 and 2021 is partly linked with increased expression of P450 alleles. BMC Infect. Dis. 22, 660 (2022).

CAS PubMed PubMed Central Google Scholar

Paton, D. G. et al. Exposing Anopheles mosquitoes to antimalarials blocks Plasmodium parasite transmission. Nature 567, 239–243 (2019). Reported that adding the antimalarial atovaquone to surfaces could lead to trans-dermal drug uptake into infected mosquitoes and block P. falciparum parasite transmission.

CAS PubMed PubMed Central Google Scholar

Paton, D. G. et al. Using an antimalarial in mosquitoes overcomes Anopheles and Plasmodium resistance to malaria control strategies. PLoS Pathog. 18, e1010609 (2022).

CAS PubMed PubMed Central Google Scholar

Adolfi, A. et al. Efficient population modification gene-drive rescue system in the malaria mosquito Anopheles stephensi. Nat. Commun. 11, 5553 (2020).

CAS PubMed PubMed Central Google Scholar

Hammond, A. et al. Gene-drive suppression of mosquito populations in large cages as a bridge between lab and field. Nat. Commun. 12, 4589 (2021).

CAS PubMed PubMed Central Google Scholar

Burrows, J. et al. A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria. Malar. J. 17, 462 (2018).

CAS PubMed PubMed Central Google Scholar

Miglianico, M. et al. Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases. Proc. Natl Acad. Sci. USA 115, E6920–E6926 (2018).

CAS PubMed PubMed Central Google Scholar

Khaligh, F. G. et al. Endectocides as a complementary intervention in the malaria control program: a systematic review. Syst. Rev. 10, 30 (2021).

PubMed PubMed Central Google Scholar

Llanos-Cuentas, A. et al. Tafenoquine versus primaquine to prevent relapse of Plasmodium vivax malaria. N. Engl. J. Med. 380, 229–241 (2019).

CAS PubMed PubMed Central Google Scholar

Lacerda, M. V. G. et al. Single-dose tafenoquine to prevent relapse of Plasmodium vivax malaria. N. Engl. J. Med. 380, 215–228 (2019).

CAS PubMed PubMed Central Google Scholar

Camarda, G. et al. Antimalarial activity of primaquine operates via a two-step biochemical relay. Nat. Commun. 10, 3226 (2019).

PubMed PubMed Central Google Scholar

Pybus, B. S. et al. The metabolism of primaquine to its active metabolite is dependent on CYP 2D6. Malar. J. 12, 212 (2013).

CAS PubMed PubMed Central Google Scholar

Silvino, A. C. R. et al. Novel insights into Plasmodium vivax therapeutic failure: CYP2D6 activity and time of exposure to malaria modulate the risk of recurrence. Antimicrob. Agents Chemother. https://doi.org/10.1128/aac.02056-19 (2020).

Article PubMed PubMed Central Google Scholar

Roth, A. et al. A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum. Nat. Commun. 9, 1837 (2018).

PubMed PubMed Central Google Scholar

Maher, S. P. et al. Probing the distinct chemosensitivity of Plasmodium vivax liver stage parasites and demonstration of 8-aminoquinoline radical cure activity in vitro. Sci. Rep. 11, 19905 (2021).

CAS PubMed PubMed Central Google Scholar

Download references

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.

University of California, San Diego, La Jolla, CA, USA

Jair L. Siqueira-Neto & Elizabeth A. Winzeler

Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch, South Africa

Kathryn J. Wicht & Kelly Chibale

South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa

Kathryn J. Wicht & Kelly Chibale

Medicines for Malaria Venture, Geneva, Switzerland

Jeremy N. Burrows

Department of Microbiology and Immunology and Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA

David A. Fidock

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

You can also search for this author in PubMed Google Scholar

The authors contributed equally to all aspects of the article.

Correspondence to Elizabeth A. Winzeler.

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.

Nature Reviews Drug Discovery thanks Paul Gilson, Philip Rosenthal and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Medicines for Malaria Venture (MMV): https://www.mmv.org/

The Drugs for Neglected Diseases initiative (DNDi): https://dndi.org/advocacy/transparency-rd-costs/

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

Siqueira-Neto, J.L., Wicht, K.J., Chibale, K. et al. Antimalarial drug discovery: progress and approaches. Nat Rev Drug Discov (2023). https://doi.org/10.1038/s41573-023-00772-9

Download citation

Accepted: 17 July 2023

Published: 31 August 2023

DOI: https://doi.org/10.1038/s41573-023-00772-9

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative