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New Medicines to Combat Malaria: An Overview of the Global Pipeline of Therapeutics

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Treatment and Prevention of Malaria

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

Over the last 5 years, there has been an increased investment in malaria medicines, with the emergence of a range of new fixed dose artemisinin combination therapies (FACTs). Of the six FACTS, two are now approved and prequalified by the WHO, with another two submitted for stringent regulator approval. Malaria treatments are therefore available to more than 160 million patients, which cure the disease in more than 98% of cases, with 3 days of therapy, and cost as little as $0.30 per treatment for infants. Molecules currently in the pipeline offer the possibility that this could be replaced by a single dose cure in the next few years. Many new compounds have entered the pipeline as a result of advances in phenotypic screening and new targets identified from the parasite genomes. Artemisinin resistance has been confirmed in Cambodia, and new classes of medicines will be needed in case artemisinin resistance spreads. The recent call for the eradication of malaria has set new objectives for the drug discovery and development field. There is an additional focus on having compounds, which can block transmission. In addition, safe medicines to kill liver stages, and block the relapse of P. vivax and P. ovale are needed, which are more convenient than the 14-day primaquine treatment, and better tolerated in G6PD-deficient patients. The next decade will be a defining one, as we implement new generations of therapies in the field, and bring forward the ones needed for the next stages of malaria eradication.

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References

  1. Maude RJ, Pontavornpinyo W, Saralamba S, Aguas R, Yeung S, Dondorp AM, Day NP, White NJ, White LJ (2009) The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia. Malar J 8:31

    Article  PubMed  Google Scholar 

  2. Oliaro P, Wells TN (2009) The global portfolio of new antimalarial medicines under development. Clin Pharm Ther 85:584–595

    Article  Google Scholar 

  3. Wells TN, Alonso PL, Gutteridge WE (2009) New medicines to improve control and contribute to the eradication of malaria. Nat Rev Drug Discov 8:879–891

    Article  PubMed  CAS  Google Scholar 

  4. White NJ (2008) Qinghaosu (artemisinin): the price of success. Science 320:330–334

    Article  PubMed  CAS  Google Scholar 

  5. World Health Organization. Malaria treatment guidelines, June 2010. http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html. Accessed 22 May 2011

  6. Tun T, Tint HS, Lin K, Kyaw TT, Myint MK, Khaing W, Tun ZW (2009) Efficacy of oral single dose therapy with artemisinin-naphthoquine phosphate in uncomplicated falciparum malaria. Acta Trop 111:275–278

    Article  PubMed  CAS  Google Scholar 

  7. Qu HY, Gao HZ, Hao GT, Li YY, Li HY, Hu JC, Wang XF, Liu WL, Liu ZY (2010) Single-dose safety, pharmacokinetics, and food effects studies of compound naphthoquine phosphate tablets in healthy volunteers. J Clin Pharmacol 50:1310–1318

    Article  PubMed  CAS  Google Scholar 

  8. Clark RL (2009) Embryotoxicity of the artemisinin antimalarials and potential consequences for use in women in the first trimester. Reprod Toxicol 28:285–296

    Article  PubMed  CAS  Google Scholar 

  9. Chico RM, Pittrof R, Greenwood B, Chandramohan D (2008) Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy. Malar J 7:255

    Article  PubMed  Google Scholar 

  10. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM; Artemisinin Resistance in Cambodia 1 (ARC1) Study Consortium (2008) Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 359:2619–2620

    Article  Google Scholar 

  11. Dondorp AM, Nosten F, Yi P, Das D, Phyo PA, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ et al (2009) Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361:455–467

    Article  PubMed  CAS  Google Scholar 

  12. Vennerstrom JL, Arbe-Barnes S, Brun R, Charman SA, Chiu FC, Chollet J, Dong Y, Dorn A, Hunziker D, Matile H et al (2004) Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430:900–904

    Article  PubMed  CAS  Google Scholar 

  13. Charman SA, Arbe-Barnes S, Bathurst IC, Brun R, Campbell M, Charman WN, Chiu FC, Chollet J, Craft JC, Creek DJ et al (2011) Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proc Natl Acad Sci USA 108:4400–4405

    Article  PubMed  CAS  Google Scholar 

  14. Nagelschmitz J, Voith B, Wensing G, Roemer A, Fugmann B, Haynes RK, Kotecka BM, Rieckmann KH, Edstein MD (2008) First assessment in humans of the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of the new artemisinin derivative artemisone. Antimicrob Agents Chemother 52:3085–3091

    Article  PubMed  CAS  Google Scholar 

  15. O’Neill PM et al. (2010) http://www.a-star.edu.sg/Portals/0/media/Press%20Release/PressRelease_UKSIN_FINAL_media.pdf

  16. Singh RP, Sabarinath S, Gautam N, Gupta RC, Singh SK (2009) Liquid chromatographic tandem mass spectrometric assay for quantification of 97/78 and its metabolite 97/63: A promising trioxane antimalarial in monkey plasma. J Chromatogr B 877:2074–2080

    Article  CAS  Google Scholar 

  17. Coslédan F, Fraisse L, Pellet A, Guillou F, Mordmüller B, Kremsner PG, Moreno A, Mazier D, Maffrand JP, Meunier B (2008) Selection of a trioxaquine as an antimalarial drug candidate. Proc Natl Acad Sci USA 105:17579–17584

    Article  PubMed  Google Scholar 

  18. Na-Bangchang K, Ruengweerayut R, Karbwang J, Chauemung A, Hutchinson D (2007) Pharmacokinetics and pharmacodynamics of fosmidomycin monotherapy and combination therapy with clindamycin in the treatment of multidrug resistant falciparum malaria. Malar J 6:70

    Article  PubMed  Google Scholar 

  19. Dive D, Biot C (2008) Ferrocene conjugates of chloroquine and other antimalarials: the development of ferroquine, a new antimalarial. ChemMedChem 3:383–391

    Article  PubMed  CAS  Google Scholar 

  20. Plouffe D, Brinker A, McNamara C, Henson K, Kato N, Kuhen K, Nagle A, Adrián F, Matzen JT, Anderson P et al (2008) 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

    Article  PubMed  CAS  Google Scholar 

  21. Gamo FJ, Sanz LM, Vidal J, Cozar C, Alarez E, Lavandera JL, Vanderwall DE, Green DVS, Kumar V, Hasan S et al (2010) Thousands of chemical starting points for antimalarial lead identification. Nature 465:305–310

    Article  PubMed  CAS  Google Scholar 

  22. Baniecki ML, Wirth DF, Clardy J (2007) High-throughput Plasmodium falciparum growth assay for malaria drug discovery. Antimicrob Agents Chemother 51:716–723

    Article  PubMed  CAS  Google Scholar 

  23. Guiguemde WA, Shelat AA, Bouck D, Duffy S, Crowther GJ, Davis PH, Smithson DC, Connelly M, Clark J, Zhu F et al (2010) Chemical genetics of Plasmodium falciparum. Nature 465:311–315

    Article  PubMed  CAS  Google Scholar 

  24. Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S et al (2002) Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498–511

    Article  PubMed  CAS  Google Scholar 

  25. Aguero F, Al-Lazikani B, Aslett M, Berriman M, Buckner FS, Campbell RK, Carmna S, Carruthers IM, Chan AW, Chen F et al (2008) Genomic-scale prioritization of drug targets: the TDR Targets database. Nat Rev Drug Discov 7:900–907

    Article  PubMed  Google Scholar 

  26. Grundner C, Perrin D, Hooft van Huijsduijnen R, Swinnen D, Gonzalez J, Gee CL, Wells TN, Alber T (2007) Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB. Structure 15:499–509

    Article  PubMed  CAS  Google Scholar 

  27. Yuthavong Y, Yuvaniyama J, Chitnumsub P, Vanichtanankul J, Chusacultanachai S, Tarnchompoo B, Vilaivan T, Kamchonwongpaisan S (2005) Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors. Parasitology 130:249–259

    Article  PubMed  CAS  Google Scholar 

  28. Deng X, Gujjar R, El Mazouni F, Kaminsky W, Malmquist NA, Goldsmith EJ, Rathod PK, Phillips MA (2009) Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J Biol Chem 284:26999–27009

    Article  PubMed  CAS  Google Scholar 

  29. Roberts L, Enserink M (2007) Malaria. Did they really say … eradication? Science 318:1544–1545

    Article  PubMed  CAS  Google Scholar 

  30. Wells TN, Burrows J, Baird JK (2010) Targeting the hypnozoite reservoir of Plasmodium vivax: the hidden obstacle to malaria elimination. Trend Parasitol 26:1471–1477

    Article  Google Scholar 

  31. Beutler E, Duparc S; G6PD Deficiency Working Group (2007) Glucose-6-phosphate dehydrogenase deficiency and antimalarial drug development. Am J Trop Med Hyg 77:779–789

    Google Scholar 

  32. Kitchener S, Nasveld P, Edstein MD (2007) Tafenoquine for the treatment of recurrent Plasmodium vivax malaria. Am J Trop Med Hyg 76:494–496

    PubMed  CAS  Google Scholar 

  33. Nanayakkara NP, Ager AL Jr, Bartlett MS, Yardley V, Croft SL, Khan IA, McChesney JD, Walker LA (2008) Antiparasitic activities and toxicities of individual enantiomers of the 8-aminoquinoline 8-[(4-amino-1-methylbutyl)amino]-6-methoxy-4-methyl-5-[3,4-dichlorophenoxy]quinoline succinate. Antimicrob Agents Chemother 52:2130–2137

    Article  PubMed  CAS  Google Scholar 

  34. Mazier D, Landau I, Druilhe P, Miltgen F, Guguen-Guillouzo C, Baccam D, Baxter J, Chigot JP, Gentilini M (1984) Cultivation of the liver forms of Plasmodium vivax in human hepatocytes. Nature 307:367–369

    Article  PubMed  CAS  Google Scholar 

  35. Dembele L, Gego A, Zeeman AM, Franetich JF, Silvi O, Rametti A, LeGrand R, Dereuddre-Bosquet N, Sauerwein R, van Gemert GJ (2011) Towards an in vitro model of Plasmodium hypnozoites suitable for drug discovery. PLoS One 6:e18162

    Article  PubMed  CAS  Google Scholar 

  36. Sinden RE (1998) Gametocytes and sexual development. In: Sherman IW (ed) Malaria: parasite biology, pathogenesis and protection. ASM, Washington, DC, pp 25–48

    Google Scholar 

  37. Dorin-Semblat D, Sicard A, Doerig C, Ranford-Cartwright L, Doerig C (2008) Disruption of the PfPK7 gene impairs schizogony and sporogony in the human malaria parasite Plasmodium falciparum. Eukaryot Cell 7:279–285

    Article  PubMed  CAS  Google Scholar 

  38. Kumar S, Molina-Cruz A, Gupta L, Rodrigues J, Barillas-Mury C (2010) A peroxidase/dual oxidase system modulates midgut epithelial immunity in Anopheles gambiae. Science 327:1644–1648

    Article  PubMed  CAS  Google Scholar 

  39. McRobert L, Taylor CJ, Deng W, Fivelman QL, Cummings RM, Polley SD, Billker O, Baker DA (2008) Gametogenesis in malaria parasites is mediated by the cGMP-dependent protein kinase. PLoS Biol 6:e139

    Article  PubMed  Google Scholar 

  40. Alonso PL, Djimde A, Kremsner P, Magill A, Milman J, Nájera J, Plowe CV, Rabinovich R, Wells T, Yeung S (2011) The malERA Consultative Group on Drugs, A research agenda for malaria eradication: drugs. PLoS Med 8:e1000402

    Article  Google Scholar 

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Acknowledgments

I would like to thank the Medicines for Malaria Research and Development team for all their insights into this article, and for the many advisors, especially our External Scientific Advisory Committee, who have done so much to transform the pipeline of antimalarial therapeutics.

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Authors and Affiliations

  1. Medicines for Malaria Venture, 20 route de Pré-Bois, Geneva, CH-1215, Switzerland

    Timothy N. C. Wells

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  1. Timothy N. C. Wells
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Correspondence to Timothy N. C. Wells .

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Editors and Affiliations

  1. Centre for Infection, Div. Cellular & Molecular Medicine, St. George's University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom

    Henry M. Staines

  2. Medical School, Dept. Infectious Diseases, St. George´s Hospital, Cranmer Terrace, London, SW17 0RE, United Kingdom

    Sanjeev Krishna

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© 2011 Springer Basel AG

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Wells, T.N.C. (2011). New Medicines to Combat Malaria: An Overview of the Global Pipeline of Therapeutics. In: Staines, H., Krishna, S. (eds) Treatment and Prevention of Malaria. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-0346-0480-2_12

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