Antimalarials Targeting the Malaria Parasite Cation ATPase P. falciparum
ATP4 (PfATP4)

Agnieszka      Zagórska; Anna      Jaromin

doi:10.2174/1568026623666221121154354

Abstract

Malaria, caused by parasites of the Plasmodium species and transmitted through the bites of infected female Anopheles mosquitoes, is still a fatal and dangerous disease in mainly tropical and subtropical regions. The widespread resistance of P. falciparum to antimalarial drugs forces the search for new molecules with activity against this parasite. While a large number of compounds can inhibit P. falciparum growth in vitro, unfortunately, only a limited number of targets have been identified so far. One of the most promising approaches has been the identification of effective inhibitors of P-type cation-transporter ATPase 4 (PfATP4) in P. falciparum. PfATP4 is a Na+ efflux pump that maintains a low cytosolic Na+ in the parasite. Thus, upon treatment with PfATP4 inhibitors, the parasites rapidly accumulate Na+, which triggers processes leading to parasite death. PfATP4 is present in the parasite plasma membrane but is absent in mammals; its exclusivity thus makes it a good antimalarial drug target.

The current review presents PfATP4 function in the context of the pharmacological influence of its inhibitors. In addition, compounds with inhibitory activities belonging to spiroindolones, dihydroisoquinolones, aminopyrazoles, pyrazoleamides, and 4-cyano-3-methylisoquinolines, are also reviewed. Particular emphasis is placed on the results of preclinical and clinical studies in which their effectiveness was tested. PfATP4-associated antimalarials rapidly cleared parasites in mouse models and preliminary human trials. These findings highlight a fundamental biochemical mechanism sensitive to pharmacological intervention that can form a medicinal chemistry approach for antimalarial drug design to create new molecules with potent PfATP4 inhibitory activity.

« Previous Next »

Graphical Abstract

[1]
World Health Organization (WHO). World malaria report., 2021. Available from: https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021

[2]
PATH’s Malaria Vaccine Initiative. Malaria parasite life cycle.,  Available from: https://www.malariavaccine.org/malaria-and-vaccines/vaccine-development/life-cycle-malaria-parasite

[3]
World Health Organization (WHO). Malaria vaccine implementation programme.,  Available from: https://www.who.int/initiatives/malaria-vaccine-implementation-programme

[4]
Chandramohan, D.; Zongo, I.; Sagara, I.; Cairns, M.; Yerbanga, R.S.; Diarra, M.; Nikièma, F.; Tapily, A.; Sompougdou, F.; Issiaka, D.; Zoungrana, C.; Sanogo, K.; Haro, A.; Kaya, M.; Sienou, A.A.; Traore, S.; Mahamar, A.; Thera, I.; Diarra, K.; Dolo, A.; Kuepfer, I.; Snell, P.; Milligan, P.; Ockenhouse, C.; Ofori-Anyinam, O.; Tinto, H.; Djimde, A.; Ouédraogo, J.B.; Dicko, A.; Greenwood, B. Seasonal malaria vaccination with or without seasonal malaria chemoprevention. N. Engl. J. Med.,  2021, 385(11), 1005-1017.
 [http://dx.doi.org/10.1056/NEJMoa2026330] [PMID: 34432975]

[5]
World Health Organization (WHO). WHO Guidelines.,  Available from: https://www.who.int/publications/who-guidelines

[6]
Khan, J.; Kaushik, M.; Singh, S.; Khan, J.; Kaushik, M.; Singh, S. Molecular Mechanisms of Action and Resistance of Antimalarial Drugs. In: Bacterial Adaptation to Co-resistance; Springer: Singapore, 2019; pp. 267-296.
 [http://dx.doi.org/10.1007/978-981-13-8503-2_14]

[7]
Spillman, N.J.; Allen, R.J.W.; Kirk, K. Na+ extrusion imposes an acid load on the intraerythrocytic malaria parasite. Mol. Biochem. Parasitol.,  2013, 189(1-2), 1-4.
 [http://dx.doi.org/10.1016/j.molbiopara.2013.04.004] [PMID: 23623918]

[8]
Teissie, J.; Tsong, T.Y. Evidence of voltage-induced channel opening in Na/K ATPase of human erythrocyte membrane. J. Membr. Biol.,  1980, 55(2), 133-140.
 [http://dx.doi.org/10.1007/BF01871155] [PMID: 6251222]

[9]
Ginsburg, H.; Stein, W.D. The new permeability pathways induced by the malaria parasite in the membrane of the infected erythrocyte: comparison of results using different experimental techniques. J. Membr. Biol.,  2004, 197, 113-134.
 [http://dx.doi.org/10.1007/s00232-003-0646-7]

[10]
Spillman, N.J.; Allen, R.J.W.; McNamara, C.W.; Yeung, B.K.S.; Winzeler, E.A.; Diagana, T.T.; Kirk, K. Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host Microbe,  2013, 13(2), 227-237.
 [http://dx.doi.org/10.1016/j.chom.2012.12.006] [PMID: 23414762]

[11]
Desai, S.A.; Rosenberg, R.L. Pore size of the malaria parasite’s nutrient channel. Proc. Natl. Acad. Sci. USA,  1997, 94(5), 2045-2049.
 [http://dx.doi.org/10.1073/pnas.94.5.2045] [PMID: 9050902]

[12]
Pillai, A.D.; Addo, R.; Sharma, P.; Nguitragool, W.; Srinivasan, P.; Desai, S.A. Malaria parasites tolerate a broad range of ionic environments and do not require host cation remodelling. Mol. Microbiol.,  2013, 88(1), 20-34.
 [http://dx.doi.org/10.1111/mmi.12159] [PMID: 23347042]

[13]
Trottein, F.; Cowman, A.F.; Cowman, A.F.; Hall, E. Molecular cloning and sequence of two novel P-type adenosinetriphosphatases from Plasmodium falciparum. Eur. J. Biochem.,  1995, 227(1-2), 214-225.
 [http://dx.doi.org/10.1111/j.1432-1033.1995.tb20379.x] [PMID: 7851389]

[14]
Trottein, F.; Thompson, J.; Cowman, A.F. Cloning of a new cation ATPase from Plasmodium falciparum: conservation of critical amino acids involved in calcium binding in mammalian organellar Ca2+-ATPases. Gene,  1995, 158(1), 133-137.
 [http://dx.doi.org/10.1016/0378-1119(95)00158-3] [PMID: 7789797]

[15]
Krishna, S.; Woodrow, C.; Webb, R.; Penny, J.; Takeyasu, K.; Kimura, M.; East, J.M. Expression and functional characterization of a Plasmodium falciparum Ca2+-ATPase (PfATP4) belonging to a subclass unique to apicomplexan organisms. J. Biol. Chem.,  2001, 276(14), 10782-10787.
 [http://dx.doi.org/10.1074/jbc.M010554200] [PMID: 11145964]

[16]
Rodríguez-Navarro, A.; Benito, B. Sodium or potassium efflux ATPase. Biochim. Biophys. Acta Biomembr.,  2010, 1798(10), 1841-1853.
 [http://dx.doi.org/10.1016/j.bbamem.2010.07.009] [PMID: 20650263]

[17]
Spillman, N.J.; Kirk, K. The malaria parasite cation ATPase PfATP4 and its role in the mechanism of action of a new arsenal of antimalarial drugs. Int. J. Parasitol. Drugs Drug Resist.,  2015, 5(3), 149-162.
 [http://dx.doi.org/10.1016/j.ijpddr.2015.07.001] [PMID: 26401486]

[18]
Tse, E.G.; Aithani, L.; Anderson, M.; Cardoso-Silva, J.; Cincilla, G.; Conduit, G.J.; Galushka, M.; Guan, D.; Hallyburton, I.; Irwin, B.W.J.; Kirk, K.; Lehane, A.M.; Lindblom, J.C.R.; Lui, R.; Matthews, S.; McCulloch, J.; Motion, A.; Ng, H.L.; Öeren, M.; Robertson, M.N.; Spadavecchio, V.; Tatsis, V.A.; van Hoorn, W.P.; Wade, A.D.; Whitehead, T.M.; Willis, P.; Todd, M.H. An open drug discovery competition: experimental validation of predictive models in a series of novel antimalarials. J. Med. Chem.,  2021, 64(22), 16450-16463.
 [http://dx.doi.org/10.1021/acs.jmedchem.1c00313] [PMID: 34748707]

[19]
Lehane, A.M.; Ridgway, M.C.; Baker, E.; Kirk, K. Diverse chemotypes disrupt ion homeostasis in the malaria parasite. Mol. Microbiol.,  2014, 94(2), 327-339.
 [http://dx.doi.org/10.1111/mmi.12765] [PMID: 25145582]

[20]
Vallières, C.; Avery, S.V. The candidate antimalarial drug mmv665909 causes oxygen-dependent mRNA mistranslation and synergizes with quinoline-derived antimalarials. Antimicrob. Agents Chemother.,  2017, 61(9), e00459-17.
 [http://dx.doi.org/10.1128/AAC.00459-17] [PMID: 28652237]

[21]
Winterberg, M.; Kirk, K. A high-sensitivity HPLC assay for measuring intracellular Na+ and K+ and its application to Plasmodium falciparum infected erythrocytes. Sci. Rep.,  2016, 6(1), 29241.
 [http://dx.doi.org/10.1038/srep29241] [PMID: 27385291]

[22]
Staines, H.M.; Ellory, J.C.; Kirk, K. Perturbation of the pump-leak balance for Na+ and K+ in malaria-infected erythrocytes. Am. J. Physiol. Cell Physiol.,  2001, 280(6), C1576-C1587.
 [http://dx.doi.org/10.1152/ajpcell.2001.280.6.C1576] [PMID: 11350753]

[23]
Zhang, Y.K.; Plattner, J.J.; Easom, E.E.; Jacobs, R.T.; Guo, D.; Freund, Y.R.; Berry, P.; Ciaravino, V.; Erve, J.C.L.; Rosenthal, P.J.; Campo, B.; Gamo, F.J.; Sanz, L.M.; Cao, J. Benzoxaborole antimalarial agents. part 5. lead optimization of novel amide pyrazinyloxy benzoxaboroles and identification of a preclinical candidate. J. Med. Chem.,  2017, 60(13), 5889-5908.
 [http://dx.doi.org/10.1021/acs.jmedchem.7b00621] [PMID: 28635296]

[24]
Vaidya, A.B.; Morrisey, J.M.; Zhang, Z.; Das, S.; Daly, T.M.; Otto, T.D.; Spillman, N.J.; Wyvratt, M.; Siegl, P.; Marfurt, J. Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. Nat. Commun.,  2014, 5, 1-10.
 [http://dx.doi.org/10.1038/ncomms6521]

[25]
Das, S.; Bhatanagar, S.; Morrisey, J.M.; Daly, T.M.; Burns, J.M., Jr; Coppens, I.; Vaidya, A.B. Na+ influx induced by new antimalarials causes rapid alterations in the cholesterol content and morphology of Plasmodium falciparum. PLoS Pathog.,  2016, 12(5), e1005647.
 [http://dx.doi.org/10.1371/journal.ppat.1005647] [PMID: 27227970]

[26]
Jiménez-Díaz, M.B.; Ebert, D.; Salinas, Y.; Pradhan, A.; Lehane, A.M.; Myrand-Lapierre, M.E.; O’Loughlin, K.G.; Shackleford, D.M.; Justino de Almeida, M.; Carrillo, A.K.; Clark, J.A.; Dennis, A.S.M.; Diep, J.; Deng, X.; Duffy, S.; Endsley, A.N.; Fedewa, G.; Guiguemde, W.A.; Gómez, M.G.; Holbrook, G.; Horst, J.; Kim, C.C.; Liu, J.; Lee, M.C.S.; Matheny, A.; Martínez, M.S.; Miller, G.; Rodríguez-Alejandre, A.; Sanz, L.; Sigal, M.; Spillman, N.J.; Stein, P.D.; Wang, Z.; Zhu, F.; Waterson, D.; Knapp, S.; Shelat, A.; Avery, V.M.; Fidock, D.A.; Gamo, F.J.; Charman, S.A.; Mirsalis, J.C.; Ma, H.; Ferrer, S.; Kirk, K.; Angulo-Barturen, I.; Kyle, D.E.; DeRisi, J.L.; Floyd, D.M.; Guy, R.K. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium. Proc. Natl. Acad. Sci. USA,  2014, 111(50), E5455-E5462.
 [http://dx.doi.org/10.1073/pnas.1414221111] [PMID: 25453091]

[27]
Rottmann, M.; McNamara, C.; Yeung, B.K.S.; Lee, M.C.S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D.M.; Dharia, N. V.; Tan, J. Spiroindolones, a potent compound class for the treatment of malaria. Science (80-.),  2010, 329, 1175-1180.
 [http://dx.doi.org/10.1126/science.1193225]

[28]
Gilson, P.R.; Kumarasingha, R.; Thompson, J.; Zhang, X.; Penington, J.S.; Kalhor, R.; Bullen, H.E.; Lehane, A.M.; Dans, M.G.; de Koning-Ward, T.F. A 4-cyano-3-methylisoquinoline inhibitor of Plasmodium falciparum growth targets the sodium efflux pump PfATP4. Sci. Reports,  2019, 9, 1-15.
 [http://dx.doi.org/10.1038/s41598-019-46500-5]

[29]
Buskes, M.J.; Harvey, K.L.; Prinz, B.; Crabb, B.S.; Gilson, P.R.; Wilson, D.J.D.; Abbott, B.M. Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum. Bioorg. Med. Chem.,  2016, 24(11), 2389-2396.
 [http://dx.doi.org/10.1016/j.bmc.2016.03.048] [PMID: 27112453]

[30]
Yeung, B.K.S.; Zou, B.; Rottmann, M.; Lakshminarayana, S.B.; Ang, S.H.; Leong, S.Y.; Tan, J.; Wong, J.; Keller-Maerki, S.; Fischli, C.; Goh, A.; Schmitt, E.K.; Krastel, P.; Francotte, E.; Kuhen, K.; Plouffe, D.; Henson, K.; Wagner, T.; Winzeler, E.A.; Petersen, F.; Brun, R.; Dartois, V.; Diagana, T.T.; Keller, T.H. Spirotetrahydro β-carbolines (spiroindolones): A new class of potent and orally efficacious compounds for the treatment of malaria. J. Med. Chem.,  2010, 53(14), 5155-5164.
 [http://dx.doi.org/10.1021/jm100410f] [PMID: 20568778]

[31]
Turner, H. Spiroindolone NITD609 is a novel antimalarial drug that targets the P-type ATPase PfATP4. Future Med. Chem.,  2016, 8(2), 227-238.
 [http://dx.doi.org/10.4155/fmc.15.177]

[32]
Dick, C.F.; Meyer-Fernandes, J.R.; Vieyra, A. The functioning of Na+-ATPases from protozoan parasites: are these pumps targets for antiparasitic drugs? Cells,  2020, 9(10), 2225.
 [http://dx.doi.org/10.3390/cells9102225] [PMID: 33023071]

[33]
White, N.J.; Pukrittayakamee, S.; Phyo, A.P.; Rueangweerayut, R.; Nosten, F.; Jittamala, P.; Jeeyapant, A.; Jain, J.P.; Lefèvre, G.; Li, R.; Magnusson, B.; Diagana, T.T.; Leong, F.J. Spiroindolone KAE609 for falciparum and vivax malaria. N. Engl. J. Med.,  2014, 371(5), 403-410.
 [http://dx.doi.org/10.1056/NEJMoa1315860] [PMID: 25075833]

[34]
Ashton, T.D.; Devine, S.M.; Möhrle, J.J.; Laleu, B.; Burrows, J.N.; Charman, S.A.; Creek, D.J.; Sleebs, B.E. The development process for discovery and clinical advancement of modern antimalarials. J. Med. Chem.,  2019, 62(23), 10526-10562.
 [http://dx.doi.org/10.1021/acs.jmedchem.9b00761] [PMID: 31385706]

[35]
Meister, S.; Plouffe, D.M.; Kuhen, K.L.; Bonamy, G.M.C.; Wu, T.; Barnes, S.W.; Bopp, S.E.; Borboa, R.; Bright, A.T.; Che, J. Imaging of plasmodium liver stages to drive next-generation antimalarial drug discovery. Science (80),  2011, 334, 1372-1377.
 [http://dx.doi.org/10.1126/science.1211936]

[36]
Huskey, S.E.W.; Zhu, C.; Fredenhagen, A.; Kühnöl, J.; Luneau, A.; Jian, Z.; Yang, Z.; Miao, Z.; Yang, F.; Jain, J.P.; Sunkara, G.; Mangold, J.B.; Stein, D.S. KAE609 (Cipargamin), a new spiroindolone agent for the treatment of malaria: evaluation of the absorption, distribution, metabolism, and excretion of a single oral 300-mg dose of [14C]KAE609 in healthy male subjects. Drug Metab. Dispos.,  2016, 44(5), 672-682.
 [http://dx.doi.org/10.1124/dmd.115.069187] [PMID: 26921387]

[37]
Schmitt, E.K.; Ndayisaba, G.; Yeka, A.; Asante, K.P.; Grobusch, M.P.; Karita, E.; Mugerwa, H.; Asiimwe, S.; Oduro, A.; Fofana, B. 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., 2021.
 [http://dx.doi.org/10.1093/cid/ciab716] [PMID: 34410358]

[38]
Flegg, J.A.; Guerin, P.J.; White, N.J.; Stepniewska, K. Standardizing the measurement of parasite clearance in falciparum malaria: The parasite clearance estimator. Malar. J.,  2011, 10(1), 339.
 [http://dx.doi.org/10.1186/1475-2875-10-339] [PMID: 22074219]

[39]
Takata, J.; Sondo, P.; Humphreys, G.S.; Burrow, R.; Maguire, B.; Hossain, M.S.; Das, D.; Commons, R.J.; Price, R.N.; Guerin, P.J. The worldwide antimalarial resistance network clinical trials publication library: a live, open-access database of Plasmodium treatment efficacy trials. Am. J. Trop. Med. Hyg.,  2020, 103(1), 359-368.
 [http://dx.doi.org/10.4269/ajtmh.19-0706] [PMID: 32431267]

[40]
McCarthy, J.S.; Abd-Rahman, A.N.; Collins, K.A.; Marquart, L.; Griffin, P.; Kümmel, A.; Fuchs, A.; Winnips, C.; Mishra, V.; Csermak-Renner, K.; Jain, J.P.; Gandhi, P. Defining the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage plasmodium falciparum. Antimicrob. Agents Chemother.,  2021, 65(2), e01423-20.
 [http://dx.doi.org/10.1128/AAC.01423-20] [PMID: 33199389]

[41]
Hien, T.T.; White, N.J.; Thuy-Nhien, N.T.; Hoa, N.T.; Thuan, P.D.; Tarning, J.; Nosten, F.; Magnusson, B.; Jain, J.P.; Hamed, K. Estimation of the in vivo MIC of cipargamin in uncomplicated plasmodium falciparum malaria. Antimicrob. Agents Chemother.,  2017, 61(2), e01940-16.
 [http://dx.doi.org/10.1128/AAC.01940-16] [PMID: 27872070]

[42]
Leong, F.J.; Li, R.; Jain, J.P.; Lefèvre, G.; Magnusson, B.; Diagana, T.T.; Pertel, P. A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel antimalarial Spiroindolone KAE609 (Cipargamin) to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. Antimicrob. Agents Chemother.,  2014, 58(10), 6209-6214.
 [http://dx.doi.org/10.1128/AAC.03393-14] [PMID: 25114127]

[43]
Ndayisaba, G.; Yeka, A.; Asante, K.P.; Grobusch, M.P.; Karita, E.; Mugerwa, H.; Asiimwe, S.; Oduro, A.; Fofana, B.; Doumbia, S.; Jain, J.P.; Barsainya, S.; Kullak-Ublick, G.A.; Su, G.; Schmitt, E.K.; Csermak, K.; Gandhi, P.; Hughes, D. 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.,  2021, 20(1), 478.
 [http://dx.doi.org/10.1186/s12936-021-04009-1] [PMID: 34930267]

[44]
Guiguemde, W.A.; Shelat, A.A.; Bouck, D.; Duffy, S.; Crowther, G.J.; Davis, P.H.; Smithson, D.C.; Connelly, M.; Clark, J.; Zhu, F.; Jiménez-Díaz, M.B.; Martinez, M.S.; Wilson, E.B.; Tripathi, A.K.; Gut, J.; Sharlow, E.R.; Bathurst, I.; Mazouni, F.E.; Fowble, J.W.; Forquer, I.; McGinley, P.L.; Castro, S.; Angulo-Barturen, I.; Ferrer, S.; Rosenthal, P.J.; DeRisi, J.L.; Sullivan, D.J.; Lazo, J.S.; Roos, D.S.; Riscoe, M.K.; Phillips, M.A.; Rathod, P.K.; Van Voorhis, W.C.; Avery, V.M.; Guy, R.K. Chemical genetics of Plasmodium falciparum. Nature,  2010, 465(7296), 311-315.
 [http://dx.doi.org/10.1038/nature09099] [PMID: 20485428]

[45]
Floyd, D.M.; Stein, P.; Wang, Z.; Liu, J.; Castro, S.; Clark, J.A.; Connelly, M.; Zhu, F.; Holbrook, G.; Matheny, A.; Sigal, M.S.; Min, J.; Dhinakaran, R.; Krishnan, S.; Bashyum, S.; Knapp, S.; Guy, R.K. Hit-to-lead studies for the antimalarial tetrahydroisoquinolone carboxanilides. J. Med. Chem.,  2016, 59(17), 7950-7962.
 [http://dx.doi.org/10.1021/acs.jmedchem.6b00752] [PMID: 27505686]

[46]
Gaur, A.H.; McCarthy, J.S.; Panetta, J.C.; Dallas, R.H.; Woodford, J.; Tang, L.; Smith, A.M.; Stewart, T.B.; Branum, K.C.; Freeman, B.B., III; Patel, N.D.; John, E.; Chalon, S.; Ost, S.; Heine, R.N.; Richardson, J.L.; Christensen, R.; Flynn, P.M.; Van Gessel, Y.; Mitasev, B.; Möhrle, J.J.; Gusovsky, F.; Bebrevska, L.; Guy, R.K. Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial. Lancet Infect. Dis.,  2020, 20(8), 964-975.
 [http://dx.doi.org/10.1016/S1473-3099(19)30611-5] [PMID: 32275867]

[47]
Nathan, B.; Bayley, J.; Waters, L.; Post, F.A. Cobicistat: A novel pharmacoenhancer for co-formulation with HIV protease and integrase inhibitors. Infect. Dis. Ther.,  2013, 2(2), 111-122.
 [http://dx.doi.org/10.1007/s40121-013-0013-7] [PMID: 25134475]

[48]
McCarthy, J.S.; Lotharius, J.; Rückle, T.; Chalon, S.; Phillips, M.A.; Elliott, S.; Sekuloski, S.; Griffin, P.; Ng, C.L.; Fidock, D.A.; Marquart, L.; Williams, N.S.; Gobeau, N.; Bebrevska, L.; Rosario, M.; Marsh, K.; Möhrle, J.J. Safety, tolerability, pharmacokinetics, and activity of the novel long-acting antimalarial DSM265: a two-part first-in-human phase 1a/1b randomised study. Lancet Infect. Dis.,  2017, 17(6), 626-635.
 [http://dx.doi.org/10.1016/S1473-3099(17)30171-8] [PMID: 28363636]

[49]
Woodford, J.; Gillman, A.; Jenvey, P.; Roberts, J.; Woolley, S.; Barber, B.E.; Fernandez, M.; Rose, S.; Thomas, P.; Anstey, N.M.; McCarthy, J.S. Positron emission tomography and magnetic resonance imaging in experimental human malaria to identify organ-specific changes in morphology and glucose metabolism: A prospective cohort study. PLoS Med.,  2021, 18(5), e1003567.
 [http://dx.doi.org/10.1371/journal.pmed.1003567] [PMID: 34038421]

[50]
Flannery, E.L.; McNamara, C.W.; Kim, S.W.; Kato, T.S.; Li, F.; Teng, C.H.; Gagaring, K.; Manary, M.J.; Barboa, R.; Meister, S.; Kuhen, K.; Vinetz, J.M.; Chatterjee, A.K.; Winzeler, E.A. Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistance to both aminopyrazole and spiroindolone antimalarials. ACS Chem. Biol.,  2015, 10(2), 413-420.
 [http://dx.doi.org/10.1021/cb500616x] [PMID: 25322084]

[51]
Kortagere, S.; Welsh, W.J.; Morrisey, J.M.; Daly, T.; Ejigiri, I.; Sinnis, P.; Vaidya, A.B.; Bergman, L.W. Structure-based design of novel small-molecule inhibitors of Plasmodium falciparum. J. Chem. Inf. Model.,  2010, 50(5), 840-849.
 [http://dx.doi.org/10.1021/ci100039k] [PMID: 20426475]

[52]
Buskes, M.J.; Harvey, K.L.; Richards, B.J.; Kalhor, R.; Christoff, R.M.; Gardhi, C.K.; Littler, D.R.; Cope, E.D.; Prinz, B.; Weiss, G.E.; O’Brien, N.J.; Crabb, B.S.; Deady, L.W.; Gilson, P.R.; Abbott, B.M. Antimalarial activity of novel 4-cyano-3-methylisoqui-noline inhibitors against Plasmodium falciparum: design, synthesis and biological evaluation. Org. Biomol. Chem.,  2016, 14(20), 4617-4639.
 [http://dx.doi.org/10.1039/C5OB02517F] [PMID: 27105169]

[53]
Medicines for Malaria Venture. Developing antimalarials to save lives.,  Available from: https://www.mmv.org/

[54]
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry and Review Staff Target Product Profile-A Strategic Development Process Tool,  2007, 72(61)

[55]
Burrows, J.N.; Hooft van Huijsduijnen, R.; Möhrle, J.J.; Oeuvray, C.; Wells, T.N.C. Designing the next generation of medicines for malaria control and eradication. Malar. J.,  2013, 12(1), 187.
 [http://dx.doi.org/10.1186/1475-2875-12-187] [PMID: 23742293]

[56]
Burrows, J.N.; Duparc, S.; Gutteridge, W.E.; Hooft Van Huijsduijnen, R.; Kaszubska, W.; Macintyre, F.; Mazzuri, S.; Möhrle, J.J.; Wells, T.N.C. New developments in anti-malarial target candidate and product profiles. Malar. J.,  2017, 16, 1-29.
 [http://dx.doi.org/10.1186/s12936-016-1675-x]

[57]
Dennis, A.S.M.; Rosling, J.E.O.; Lehane, A.M.; Kirk, K. Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis. Sci. Rep.,  2018, 8(1), 8795.
 [http://dx.doi.org/10.1038/s41598-018-26819-1] [PMID: 29892073]

[58]
Sacchetto, R.; Bertipaglia, I.; Giannetti, S.; Cendron, L.; Mascarello, F.; Damiani, E.; Carafoli, E.; Zanotti, G. Crystal structure of sarcoplasmic reticulum Ca2+-ATPase (SERCA) from bovine muscle. J. Struct. Biol.,  2012, 178(1), 38-44.
 [http://dx.doi.org/10.1016/j.jsb.2012.02.008] [PMID: 22387132]

[59]
UniProtKB.  Available from: https://www.uniprot.org/uniprot/?query=PfATP4&amp;sort=score

[60]
Surur, A.S.; Huluka, S.A.; Mitku, M.L.; Asres, K. Indole: The after next scaffold of antiplasmodial agents? Drug Des. Devel. Ther.,  2020, 14, 4855-4867.
 [http://dx.doi.org/10.2147/DDDT.S278588] [PMID: 33204071]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1568026623666221121154354	Print ISSN 1568-0266
Publisher Name Bentham Science Publisher	Online ISSN 1873-4294

Current Topics in Medicinal Chemistry

Antimalarials Targeting the Malaria Parasite Cation ATPase P. falciparum ATP4 (PfATP4)

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract