Abstract
Malaria is a mosquito-borne disease that wreaks devastation all over the world. Plasmodium, the disease’s causative agent, is spread via female Anopheles mosquito bites. Despite the fact that malaria is preventable and treatable, the crisis of antimalarial drug resistance is growing, necessitating active research for new and affordable medications that target the parasite’s specific pathways. Several new therapeutic targets have been discovered since the genome sequencing was completed in 2004. Through computational research of Plasmodium falciparum metabolism, several prospective drug development starting points have also been identified. As a result, drug development has shifted from serendipity/whole-cell screening of vast libraries to a new era of target-focused investigations, in which the method is more systematic and based on parasite genome knowledge. In this chapter, we discuss the current methodologies in antimalarial drug discovery.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Andrews KA, Wesche D, McCarthy J et al (2018) Model-informed drug development for malaria therapeutics. Annu Rev Pharmacol Toxicol 58:567–582
Baker DA (2010) Malaria gametocytogenesis. Mol Biochem Parasitol 172(2):57–65
Baldwin SA, McConkey GA, Cass CE et al (2007) Nucleoside transport as a potential target for chemotherapy in malaria. Curr Pharm Des 13(6):569–580
Bartoloni A, Zammarchi L (2012) Clinical aspects of uncomplicated and severe malaria. Mediterr J Hematol Infect Dis 4(1):e2012026
Biagini GA, ONeill PM, Nzila A et al (2003) Antimalarial chemotherapy: young guns or back to the future? Trends Parasitol 19(11):479–487
Buchholz K, Burke TA, Williamson KC et al (2011) A high-throughput screen targeting malaria transmission stages opens new avenues for drug development. J Infect Dis 203(10):1445–1453
Burrows JN, Duparc S, Gutteridge WE et al (2017) New developments in anti-malarial target candidate and product profiles. Malar J 16:26
Canduri F, Perez PC et al (2007) Protein kinases as targets for antiparasitic chemotherapy drugs. Curr Drug Targets 8(3):389–398
Cowman AF, Morry MJ, Biggs BA et al (1988) Amino acid changes linked to pyrimethamine resistance in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum. Proc Natl Acad Sci U S A 85(23):9109–9113
Cui L, Mharakurwa S et al (2015) Antimalarial drug resistance: literature review and activities and findings of the ICEMR Network. Am J Trop Med Hyg 93(3 Suppl):57–68
Dembele L, Gego A, Zeeman AM et al (2011) Towards an in vitro model of Plasmodium hypnozoites suitable for drug discovery. PLoS One 3:e18162
Dhillon GP (2008) National Vector Borne Disease Control Programme—a glimpse. Directorate of National Vector Borne Disease Control Programme Directorate General of Health Services Ministry of Health & Family Welfare Government of India
Flannery EL, Chatterjee AK, Winzeler EA (2013) Antimalarial drug discovery - approaches and progress towards new medicines. Nat Rev Microbiol 11(12):849–862
Gelb MH, Hol WG (2002) Parasitology. Drugs to combat tropical protozoan parasites. Science 297(5580):343–344
Gysin J (1998) In: Sherman I (ed) Malaria: parasite biology, pathogenesis and protection, vol 419. ASM, Washington DC, p 441
Hassett MR, Roepe PD (2019) Origin and spread of evolving artemisinin-resistant Plasmodium falciparum malarial parasites in Southeast Asia. Am J Trop Med 101(6):1204
Huthmacher C, Hoppe A et al (2010) Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis. BMC Syst Biol 4:120
Jana S, Paliwal J (2007) Novel molecular targets for antimalarial chemotherapy. Int J Antimicrob Agents 30(1):4–10
Khera HK, Singh SK, Singh S (2019) Chorismate synthase from malaria parasites is bifunctional enzyme. Mol Biochem Parasitol 233:111202
Khera HK, Singh SK et al (2016) Conserved cysteine residues in malaria Chorismate synthase indicate their important role in protein structure and function. Indian J Biochem Biophys 53:161–168
Khera HK, Singh SK et al (2017) A HRMS-based method for determination of chorismate synthase activity. Protein Pept Lett 23(3):229–234
Korsinczky M, Chen N, Kotecka B et al (2000) Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother 44(8):2100–2108
Lucchi NW, Oberstaller J, Kissinger JC et al (2013) Malaria diagnostics and surveillance in the post-genomic era. Public Health Genomics 16(1-2):37–43
McCarthy JS, Marquart L, Sekuloski S et al (2016) Linking murine and human Plasmodium falciparum challenge models in a translational path for antimalarial drug development. Antimicrob Agents Chemother 60:3669–3675
Mita T, Tanabe K (2012) Evolution of Plasmodium falciparum drug resistance: implications for the development and containment of artemisinin resistance. Jpn J Infect Dis 65(6):465–475
Nallan L, Bauer KD, Bendale P et al (2005) Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. J Med Chem 48(11):3704–3713
Newby G, Bennett A, Larson E et al (2016) The path to eradication: a progress report on the malaria-eliminating countries. Lancet 387(10029):1775–1784
Nguyen-Dinh P, Payne D (1980) Pyrimethamine sensitivity in Plasmodium falciparum: determination in vitro by a modified 48-hour test. Bull World Health Organ 58(6):909–912
Oliveira JS, Vasconcelos IB, Moreira IS et al (2007) Enoyl reductases as targets for the development of anti-tubercular and anti-malarial agents. Curr Drug Targets 8(3):399–411
Operational Manual for Malaria Elimination in India (2016) (Version 1) Directorate of National Vector Borne Disease Control Programme Directorate General of Health Services Ministry of Health & Family Welfare Government of India
Packard RM (2014) The origins of antimalarial-drug resistance. N Engl J Med 371:397–399
Peatey CL, Spicer TP, Hodder PS et al (2011) A high-throughput assay for the identification of drugs against late-stage Plasmodium falciparum gametocytes. Mol Biochem Parasitol 180(2):127–131
Peters W, Robinson BL (1999) In: Zak O, Sande M (eds) Handbook of animal models of infection. Academic Press, London, pp 757–773
Rosenthal PJ, Sijwali PS, Singh A et al (2002) Cysteine proteases of malaria parasites: targets for chemotherapy. Curr Pharm Des 8(18):1659–1672
Sinha S, Sarma P, Sehgal R et al (2017) Development in assay methods for in vitro antimalarial drug efficacy testing: a systematic review. Front Pharmacol 23(8):754
Stone WJ, Eldering M, van Gemert GJ et al (2013) The relevance and applicability of oocyst prevalence as a read-out for mosquito feeding assays. Sci Rep 3:3418
Tanaka TQ, Williamson KC (2011) A malaria gametocytocidal assay using oxidoreduction indicator, alamarBlue. Mol Biochem Parasitol 177(2):160–163
Trouiller P, Olliaro P, Torreele E (2002) Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet 359(9324):2188–2194
Vieira MD, Kim MJ, Apparaju S et al (2014) PBPK model describes the effects of comedication and genetic polymorphism on systemic exposure of drugs that undergo multiple clearance pathways. Clin Pharmacol Ther 95:550–557
Wadi I, Nath M, Anvikar AR et al (2019) Recent advances in transmission-blocking drugs for malaria elimination. Future Med Chem 11(23):3047–3089
Wagner C, Pan Y, Hsu V et al (2015) Predicting the effect of cytochrome P450 inhibitors on substrate drugs: analysis of physiologically based pharmacokinetic modeling submissions to the US Food and Drug Administration. Clin Pharmacokinet 54:117–127
Wagner C, Pan Y, Hsu V et al (2016) Predicting the effect of CYP3A inducers on the pharmacokinetics of substrate drugs using physiologically based pharmacokinetic (PBPK) modeling: an analysis of PBPK submissions to the US FDA. Clin Pharmacokinet 55:475–483
Wengelnik K, Vidal V, Ancelin ML et al (2002) A class of potent antimalarials and their specific accumulation in infected erythrocytes. Science 295(5558):1311–1314
White NJ (2004) Antimalarial drug resistance. J Clin Invest 113(8):1084–1092
White NJ, Pukrittayakamee S, Hien TT et al (2014) Malaria. Lancet 383(9918):723–735
World Health Organization (2015) Guidelines for the treatment of malaria
World Health Organization (2020) World malaria report
Acknowledgements
HKK thank Tata Institute for Genetics and Society-Centre at inStem, Bengaluru for its continued support and providing a wonderful research environment.
Conflict of Interest
The authors declare no conflict of interest.
Authors Contribution
HKK conceived and wrote the manuscript. AKS contributed to figures. SS provided valuable inputs for the chapter.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Khera, H.K., Srivastava, A.K., Singh, S. (2023). Antimalarial Drug Discovery and Development: From Bench to Bedside. In: Rajput, V.S., Runthala, A. (eds) Drugs and a Methodological Compendium . Springer, Singapore. https://doi.org/10.1007/978-981-19-7952-1_16
Download citation
DOI: https://doi.org/10.1007/978-981-19-7952-1_16
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-19-7951-4
Online ISBN: 978-981-19-7952-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)