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In malaria, several protein kinases are under investigation as potential drug targets, and an inhibitor of Plasmodium phosphatidylinositol 4-kinase type III beta (PI4KIII\u03b2) is currently in phase 2 clinical studies. In this Perspective, we review the potential of kinases as drug targets for the treatment of malaria. Kinases are known to be readily druggable, and many are essential for parasite survival. A key challenge in the design of Plasmodium kinase inhibitors is obtaining selectivity over the corresponding human orthologue(s) and other human kinases due to the highly conserved nature of the shared ATP binding site. Notwithstanding this, there are some notable differences between the Plasmodium and human kinome that may be exploitable. There is also the potential for designed polypharmacology, where several Plasmodium kinases are inhibited by the same drug. Prior to starting the drug discovery process, it is important to carefully assess potential kinase targets to ensure that the inhibition of the desired kinase will kill the parasites in the required life-cycle stages with a sufficiently fast rate of kill. Here, we highlight key target attributes and experimental approaches to consider and summarize the progress that has been made targeting Plasmodium PI4KIII\u03b2, cGMP-dependent protein kinase, and cyclin-dependent-like kinase 3.<\/jats:p>","DOI":"10.1021\/acsinfecdis.0c00724","type":"journal-article","created":{"date-parts":[[2021,2,16]],"date-time":"2021-02-16T18:13:30Z","timestamp":1613499210000},"page":"518-534","source":"Crossref","is-referenced-by-count":98,"title":["<i>Plasmodium<\/i>\n                    Kinases as Potential Drug\nTargets for Malaria: Challenges and Opportunities"],"prefix":"10.1021","volume":"7","author":[{"given":"Lauren B.","family":"Arendse","sequence":"first","affiliation":[{"name":"University of Cape Town , , Rondebosch, , ,","place":["Cape Town, Western Cape, South Africa, 7701"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8810-5605","authenticated-orcid":true,"given":"Susan","family":"Wyllie","sequence":"additional","affiliation":[{"name":"University of Dundee , , ,","place":["Dundee, United Kingdom, DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1327-4727","authenticated-orcid":true,"given":"Kelly","family":"Chibale","sequence":"additional","affiliation":[{"name":"University of Cape Town , , Rondebosch, , ,","place":["Cape Town, Western Cape, South Africa, 7701"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5238-1314","authenticated-orcid":true,"given":"Ian H.","family":"Gilbert","sequence":"additional","affiliation":[{"name":"University of Dundee , , ,","place":["Dundee, United Kingdom, DD1 5EH"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2021,2,16]]},"reference":[{"key":"2026090216345329600_cit1","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/s41586-018-0327-4","article-title":"Challenges\nand recent progress in drug discovery for tropical diseases","volume":"559","author":"De Rycker","year":"2018","journal-title":"Nature"},{"key":"2026090216345329600_cit2","volume-title":"World Malaria Report 2019","author":"WHO.","year":"2019"},{"key":"2026090216345329600_cit3","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s00281-020-00796-y","article-title":"Implications\nof asymptomatic infection for the natural history of selected parasitic\ntropical diseases","volume":"42","author":"Alvar","year":"2020","journal-title":"Semin. Immunopathol."},{"key":"2026090216345329600_cit4","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1021\/acsinfecdis.9b00371","article-title":"Setting\nOur Sights on Infectious Diseases","volume":"6","author":"De Rycker","year":"2020","journal-title":"ACS Infect.\nDis."},{"key":"2026090216345329600_cit5","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1038\/s41591-020-1005-2","article-title":"Emergence and clonal expansion of\nin vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda","volume":"26","author":"Uwimana","year":"2020","journal-title":"Nat. Med."},{"key":"2026090216345329600_cit6","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12936-016-1675-x","article-title":"New developments in anti-malarial target candidate\nand product profiles","volume":"16","author":"Burrows","year":"2017","journal-title":"Malar. J."},{"key":"2026090216345329600_cit7","doi-asserted-by":"publisher","first-page":"7719","DOI":"10.1021\/jm400362b","article-title":"Drug discovery\nfor neglected diseases: Molecular target-based and phenotypic approaches","volume":"56","author":"Gilbert","year":"2013","journal-title":"J. Med. Chem."},{"key":"2026090216345329600_cit8","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad9735","article-title":"Antimalarial efficacy of MMV390048,\nan inhibitor of Plasmodium phosphatidylinositol 4-kinase","volume":"9","author":"Paquet","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"2026090216345329600_cit9","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01896-19","article-title":"Safety,\ntolerability, pharmacokinetics and antimalarial activity of the novel Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048\nin healthy volunteers","volume":"64","author":"Sinxadi","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090216345329600_cit10","doi-asserted-by":"publisher","first-page":"33189","DOI":"10.1038\/srep33189","article-title":"Plasmodium falciparum Choline Kinase\nInhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing\nParasite Death","volume":"6","author":"Serra\u0301n-Aguilera","year":"2016","journal-title":"Sci. Rep."},{"key":"2026090216345329600_cit11","doi-asserted-by":"publisher","first-page":"613","DOI":"10.3390\/cryst10070613","article-title":"Crystal Structure of the Apo and\nthe ADP-Bound Form of Choline Kinase from Plasmodium falciparum","volume":"10","author":"Torretta","year":"2020","journal-title":"Crystals"},{"key":"2026090216345329600_cit12","doi-asserted-by":"publisher","first-page":"3731","DOI":"10.1128\/AAC.00662-13","article-title":"Interrogating a hexokinase-selected small-molecule\nlibrary for inhibitors of Plasmodium falciparum hexokinase","volume":"57","author":"Harris","year":"2013","journal-title":"Antimicrob. 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Chem."},{"key":"2026090216345329600_cit15","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/1471-2164-5-79","article-title":"Protein kinases of\nthe human malaria parasite Plasmodium falciparum:\nthe kinome of a divergent eukaryote","volume":"5","author":"Ward","year":"2004","journal-title":"BMC Genomics"},{"key":"2026090216345329600_cit16","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1002\/prot.20278","article-title":"A genomic perspective of protein kinases in Plasmodium falciparum","volume":"58","author":"Anamika","year":"2005","journal-title":"Proteins: Struct., Funct., Genet."},{"key":"2026090216345329600_cit17","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/j.micinf.2012.04.007","article-title":"The kinomes\nof apicomplexan parasites","volume":"14","author":"Miranda-Saavedra","year":"2012","journal-title":"Microbes Infect."},{"key":"2026090216345329600_cit18","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1007\/s002390010211","article-title":"Molecular evolution of calmodulin-like domain protein\nkinases (CDPKs) in plants and protists","volume":"53","author":"Zhang","year":"2001","journal-title":"J. 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Rep."},{"key":"2026090216345329600_cit32","doi-asserted-by":"publisher","first-page":"2494","DOI":"10.1021\/acs.biochem.0c00259","article-title":"Heterologous Expression, Purification, and Functional\nAnalysis of the Plasmodium falciparum Phosphatidylinositol\n4-Kinase III\u00df","volume":"59","author":"Sternberg","year":"2020","journal-title":"Biochemistry"},{"key":"2026090216345329600_cit33","doi-asserted-by":"publisher","DOI":"10.5936\/csbj.201308002","article-title":"Autophagy in Plasmodium, a multifunctional pathway?","volume":"8","author":"Hain","year":"2013","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"2026090216345329600_cit34","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.1182\/blood-2009-08-238972","article-title":"PfPI3K, a\nphosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin\ntrafficking","volume":"115","author":"Vaid","year":"2010","journal-title":"Blood"},{"key":"2026090216345329600_cit35","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/nature14412","article-title":"A molecular mechanism of artemisinin resistance\nin Plasmodium falciparum malaria","volume":"520","author":"Mbengue","year":"2015","journal-title":"Nature"},{"key":"2026090216345329600_cit36","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1126\/science.aax4735","article-title":"A Kelch13-defined endocytosis pathway mediates\nartemisinin resistance in malaria parasites","volume":"367","author":"Birnbaum","year":"2020","journal-title":"Science"},{"key":"2026090216345329600_cit37","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/j.ijpara.2008.11.015","article-title":"A unique phosphatidylinositol 4-phosphate 5-kinase\nis activated by ADP-ribosylation factor in Plasmodium falciparum","volume":"39","author":"Leber","year":"2009","journal-title":"Int. J. Parasitol."},{"key":"2026090216345329600_cit38","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1096\/fasebj.9.8.7768349","article-title":"Protein kinases 6. The eukaryotic protein kinase superfamily:\nkinase (catalytic) domain structure and classification","volume":"9","author":"Hanks","year":"1995","journal-title":"FASEB J."},{"key":"2026090216345329600_cit39","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.bbapap.2009.10.017","article-title":"Defining the conserved internal architecture of a protein\nkinase","volume":"1804","author":"Kornev","year":"2010","journal-title":"Biochim. Biophys. Acta, Proteins Proteomics"},{"key":"2026090216345329600_cit40","doi-asserted-by":"publisher","first-page":"104609","DOI":"10.1016\/j.phrs.2019.104609","article-title":"Properties\nof FDA-approved small molecule protein kinase inhibitors: A 2020 update","volume":"152","author":"Roskoski","year":"2020","journal-title":"Pharmacol. 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Natl. Acad.\nSci. U. S. A."},{"key":"2026090216345329600_cit46","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1126\/science.1862342","article-title":"Crystal structure of the catalytic\nsubunit of cyclic adenosine monophosphate-dependent protein kinase","volume":"253","author":"Knighton","year":"1991","journal-title":"Science"},{"key":"2026090216345329600_cit47","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/35030148","article-title":"A chemical\nswitch for inhibitor-sensitive alleles of any protein kinase","volume":"407","author":"Bishop","year":"2000","journal-title":"Nature"},{"key":"2026090216345329600_cit48","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.exppara.2017.01.001","article-title":"Extended-spectrum\nantiprotozoal bumped kinase inhibitors: A review","volume":"180","author":"Van Voorhis","year":"2017","journal-title":"Exp. 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