DRUG DEVELOPMENT RESEARCH 71:1–3 (2010)

Editorial

Malaria Drugs: Clues From Malaria Resistance GeneticsDavid Gurwitz�

Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine,Tel-Aviv University, Tel Aviv 69978, Israel

ABSTRACT New treatments for malaria are desperately needed. Malaria drug design can be assistedby knowledge on protective host genotypes. Individuals immune to severe malaria, being only mildlyaffected by the parasite infection, may carry alleles that provide protection from severe disease, which mayprovide clues for drug discovery. Lessons about protective genotypes have improved our understanding onthe transmission and pathogenicity of the human immunodeficiency virus and have led to novel drugdesign. Similarly, clues from malaria protective genes may help in the design of new malaria therapies.Drug Dev Res 71:1–3, 2010. r 2009 Wiley-Liss, Inc.

Key words: malaria resistance; Plasmodium falciparum; Plasmodium vivax; sickle cell hemoglobin; Duffy antigen;glucose-6-phosphate dehydrogenase; glycolysis inhibitors

URGENT NEED FOR NEW MALARIA DRUGS

In spite of continued efforts to eradicate malaria,it remains a major cause of morbidity and mortality inlarge areas, in particular in sub-Saharan Africa andSoutheast Asia. The World Health Organization(WHO) estimates that in 2006 there were approxi-mately 247 million cases of malaria and 881,000malaria-related deaths globally, with the majority ofthis death toll (91%) being due to Plasmodiumfalciparum infections and 86% of malaria morbiditybeing in Africa, 9% in Southeast Asia and the 3% in theMiddle East [WHO, 2008]. The risk of death frommalaria is far higher in Africa than in other regions;88% of malaria-related deaths in Africa during 2006occurred among children under the age of 5 years,compared with only 16–40% of malaria death occurringin young children in South-Asian countries [WHO,2008]. As evident from the reviews in the currentspecial issue of Drug Development Research, we arefaced with an urgent need to find and develop newmalaria drugs and drug combinations, as the resistanceto artemisinins and its derivatives appears to bespreading in Southeast Asia and may reach Africa[Maude et al., 2010; Warsame et al., 2010], and as effortsto develop malaria vaccine have not been successful.There are several leads for additional drug targetsattacking various pathways of the malaria parasite, someof which are also described in the current issue.

However, we should also look beyond parasite targets:the host physiology, in particular red blood cellsproteins, should also be considered when searching fornew malaria drug targets, and the best clues may comefrom knowledge on malaria resistance genetics.

CLUES FROM RESISTANCE GENETICS

Clues for new malaria drugs may come fromstudies on malaria resistance genetics. Individuals whoare only mildly affected by the parasite infection maycarry polymorphic alleles protecting them from severedisease, and knowledge about such genotypes mayserve as leads for new drug discovery. A recent reviewby Anthony Allison, a pioneer of malaria resistanceepidemiology and genetics, covers the current knowl-edge on the genetics of malaria resistance [Allison,2009]. Other comprehensive reviews on the genetics ofmalaria resistance were recently published [Bongfenet al., 2009; Faik et al., 2009]. A few notable examplesare illustrated here to illuminate the potential of suchknowledge for malaria drug development.

DDR

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ddr.20353

�Correspondence to: David Gurwitz, Department ofHuman Molecular Genetics and Biochemistry, Sackler Facultyof Medicine, Tel-Aviv University, Tel Aviv 69978, Israel.E-mail: gurwitz@post.tau.ac.il

�c 2009 Wiley-Liss, Inc.

A well-known example for malaria resistance isthe protective effect of carrying the sickle cellhemoglobin (HbSA genotype), which confers resistanceto severe Plasmodium falciparum malarial anemia andrelated mortality in children [Aidoo et al., 2002].Accordingly, high frequencies of sickle-cell heterozy-gotes (20% or more) were observed in populationsliving near the malaria-endemic coast of Kenya andLake Victoria in contrast to the low frequencies ofsickle-cell heterozygotes observed in the Kenyan high-lands where malaria is uncommon [Allison, 2009].Protection from severe malaria was also observed incarriers of a(1)-thalassemia, a condition characterizedby reduced production of the normal a-globin compo-nent of hemoglobin [Williams et al., 2005a]. Themechanism underlying this resistance remains unclear;observations suggest that malaria protection by theHbAS genotype involves the enhancement of not onlyinnate but also acquired immunity to the parasite[Williams et al., 2005b].

Another intriguing clue to malaria resistancecomes from studies on the resistance to Plasmodiumvivax malaria afforded by homozygous deficiency in theDuffy antigen [Langhi and Bordin, 2006]. The Duffyblood group antigen is a chemokine receptor thatfunctions as a cellular receptor for the P. vivax parasite.Indeed, despite P. vivax being widespread throughoutthe tropical and subtropical world, it is absent fromWest Africa, where more than 95% of the population isDuffy antigen negative. Further clues to the role ofgenetic variation in chemokine receptors come fromstudies in nonhuman primates. A recent study inbaboons reported that a variation in the cis-regulatoryregion of the baboon FY gene, coding for a chemokinereceptor expressed on the erythrocyte surface andknown as the entry point for the malarial parasiteP. vivax, was associated with reduced susceptibility toHepatocystis, a malaria-like pathogen that is commonin baboons [Tung et al., 2009]. It is thus plausible thatchemokine antagonists may be developed as potentialmalaria drugs—as part of combination therapy strate-gies—similarly to the potential of CCR5 antagonists asHIV drugs [Dhami et al., 2009].

Genetic deficiency in glucose-6-phosphate dehy-drogenase (G6PD) may also affect malaria resistance.Mature red blood cells lack mitochondria and thereforedepend on glycolysis for their ATP, making G6PD acrucial enzyme. G6PD deficiency is the most commonhuman genetic deficiency and is estimated to affectabout 400 million people globally. The G6PD gene islocated on the X-chromosome, so that the deficiency isfar more common in men. Several mutations at thislocus have been described, and two mutations wereobserved in up to 20% of certain African and

Mediterranean populations; these are termed the Aand Med mutations [Tishkoff et al., 2001]. Thedistribution of G6PD deficiency in African populationssuggests that selection related to malaria resistance isinvolved, as lower P. falciparum burden was observedin G6PD-deficient East and West Africans comparedwith those with the normal G6PD activities [Allisonand Clyde, 1961]. Notably, the intraerythrocytic stageof the malaria parasite relies on a constant supply ofglucose and on glycolysis for ATP generation. Pre-liminary studies suggest a potential therapeutic effectof the glycolysis inhibitors 2-deoxy-D-glucose and2-fluoro-2-deoxy-D-glucose against P. falciparummalaria [van Schalkwyk et al., 2008]. The option forusing glycolysis inhibitors as part of combinationtherapeutics in the treatment of malaria deserves tobe further examined.

Among other heritable factors influencing malariaresistance are the major histocompatibility complex(MHC) [Allison, 2009]. Better knowledge about howthe variation in MHC genes affect malaria resistancecan prove useful for developing new malaria drugs.

CONCLUSIONS

The development of new malaria drugs shouldconsider not only parasite targets but also human hosttargets, in particular erythrocyte targets, on which theparasite relies for erythrocyte entry and supply ofenergy and nutrients. Knowledge from epidemiologicalstudies on gene alleles conferring resistance to severemalaria, and on the mechanisms underlying suchprotection, may become valuable leads for the designof new malaria drugs.

REFERENCES

Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO,Kariuki S, Nahlen BL, Lal AA, Udhayakumar V. 2002. Protectiveeffects of the sickle cell gene against malaria morbidity andmortality. Lancet 359:1311–1312.

Allison AC, Clyde DF. 1961. Malaria in African children deficient inglucose-6-phosphate dehydrogenase. BMJ 1:1546–1549.

Allison AC. 2009. Genetic control of resistance to human malaria.Curr Opin Immunol (in press) [Epub 11 May 2009].

Bongfen SE, Laroque A, Berghout J, Gros P. 2009. Genetic andgenomic analyses of host–pathogen interactions in malaria. TrendsParasitol 25:417–422.

Dhami H, Fritz CE, Gankin B, Pak SH, Yi W, Seya MJ, Raffa RB,Nagar S. 2009. The chemokine system and CCR5 antagonists:potential in HIV treatment and other novel therapies. J ClinPharm Ther 34:147–160.

Faik I, de Carvalho EG, Kun JF. 2009. Parasite–host interaction inmalaria: genetic clues and copy number variation. Genome Med 1:82.

Langhi Jr DM, Bordin JO. 2006. Duffy blood group and malaria.Hematology 11:389–398.

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Maude R, Woodrow CJ, White LJ. 2010. The artemisinins: preservingthe ‘‘magic bullet.’’ Drug Dev Res 71:12–19 (this issue).

Tishkoff SA, Varkonyi R, Cahinhinan N, Abbes S, Argyropoulos G,Destro-Bisol G, Drousiotou A, Dangerfield B, Lefranc G,Loiselet J, Piro A, Stoneking M, Tagarelli A, Tagarelli G,Touma EH, Williams SM, Clark AG. 2001. Haplotype diversityand linkage disequilibrium at human G6PD: recent origin ofalleles that confer malarial resistance. Science 293:455–462.

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WHO. 2008. World malaria report. Geneva, Switzerland:World Health Organization. http://apps.who.int/malaria/wmr2008/malaria2008.pdf.

Williams TN, Mwangi TW, Wambua S, Peto TE, Weatherall DJ,Gupta S, Recker M, Penman BS, Uyoga S, Macharia A,Mwacharo JK, Snow RW, Marsh K. 2005a. Negative epistasisbetween the malaria-protective effects of alpha1-thalassemia andthe sickle cell trait. Nat Genet 37:1253–1257.

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