Chemical Genomic Profiling for Antimalarial Therapies, Response Signatures, and Molecular Targets

Yuan, Jing; Cheng, Ken Chih-Chien; Johnson, Ronald L.; Huang, Ruili; Pattaradilokrat, Sittiporn; Liu, Anna; Guha, Rajarshi; Fidock, David A.; Inglese, James; Wellems, Thomas E.; Austin, Christopher P.; Su, Xin-zhuan

doi:10.1126/science.1205216

Cited by 131 publications

(142 citation statements)

References 41 publications

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“…Not surprisingly, drugs with similar chemical structures (e.g., halofantrine, lumefantrine, and mefloquine) show a strong correlation in responses (Fig. S2), as has previously been observed (6,7), and provide the opportunity for cross-validation of SNPs identified in association studies.…”

Section: Resultssupporting

confidence: 66%

“…In P. falciparum, however, array-based GWAS is severely limited by the relatively short extent of LD (5)(6)(7)(8). Lacking that correlation between genetic markers, genotyping arrays usually cannot detect associations with untyped markers, effectively limiting inferences to markers actually present on the array; even the highest density P. falciparum array reported to date found that LD between adjacent markers on the array was too weak for tagging in African populations (6).…”

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confidence: 99%

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Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

Park

Lukens

Neafsey

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

104

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Through rapid genetic adaptation and natural selection, the Plasmodium falciparum parasite-the deadliest of those that cause malaria-is able to develop resistance to antimalarial drugs, thwarting present efforts to control it. Genome-wide association studies (GWAS) provide a critical hypothesis-generating tool for understanding how this occurs. However, in P. falciparum, the limited amount of linkage disequilibrium hinders the power of traditional array-based GWAS. Here, we demonstrate the feasibility and power improvements gained by using whole-genome sequencing for association studies. We analyzed data from 45 Senegalese parasites and identified genetic changes associated with the parasites' in vitro response to 12 different antimalarials. To further increase statistical power, we adapted a common test for natural selection, XP-EHH (cross-population extended haplotype homozygosity), and used it to identify genomic regions associated with resistance to drugs. Using this sequence-based approach and the combination of association and selection-based tests, we detected several loci associated with drug resistance. These loci included the previously known signals at pfcrt, dhfr, and pfmdr1, as well as many genes not previously implicated in drug-resistance roles, including genes in the ubiquitination pathway. Based on the success of the analysis presented in this study, and on the demonstrated shortcomings of array-based approaches, we argue for a complete transition to sequence-based GWAS for small, low linkage-disequilibrium genomes like that of P. falciparum.

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Section: Resultssupporting

confidence: 66%

mentioning

confidence: 99%

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

Park

Lukens

Neafsey

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

104

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“…Earlier GWAS using in vitro resistance phenotypes (16,17,19) found associations between SNPs in several genes and IC 50 of DHA and other artemisinin derivatives, but none were in our topranked signatures of selection or in LD windows corresponding to our GWAS hits. This discordance is likely explained by the use of different resistance phenotypes.…”

Section: Discussionmentioning

confidence: 62%

“…The complex parasite population structure observed in Cambodia cannot be explained by grouping parasites from the two Cambodian sites, which are in close geographic proximity, and the same structure patterns were observed within each site individually. Previous GWAS examining in vitro susceptibility to artemisinins have also noted multiple populations of parasites in Cambodia (16,17). This complex population structure in Cambodia warrants further investigation.…”

Section: Discussionmentioning

confidence: 88%

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

Takala-Harrison

Clark

Jacob

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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253

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The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.drug resistance | genome-wide association | molecular markers

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“…7 Whether these effects are due to PfCRT-mediated drug efflux and/or the inhibition of the transporter's normal function (which is essential for the survival of the parasite, but currently unknown) remains unclear.…”

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confidence: 99%

Chlorpheniramine Analogues Reverse Chloroquine Resistance inPlasmodium falciparumby Inhibiting PfCRT

Deane

Summers

Lehane

et al. 2014

ACS Med. Chem. Lett.

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ABSTRACT:The emergence and spread of malaria parasites that are resistant to chloroquine (CQ) has been a disaster for world health. The antihistamine chlorpheniramine (CP) partially resensitizes CQ-resistant (CQR) parasites to CQ but possesses little intrinsic antiplasmodial activity. Mutations in the parasite's CQ resistance transporter (PfCRT) confer resistance to CQ by enabling the protein to transport the drug away from its site of action, and it is thought that resistance-reversers such as CP exert their effect by blocking this CQ transport activity. Here, a series of new structural analogues and homologues of CP have been synthesized. We show that these compounds (along with other in vitro CQ resistance-reversers) inhibit the transport of CQ via a resistanceconferring form of PfCRT expressed in Xenopus laevis oocytes. Furthermore, the level of PfCRT-inhibition was found to correlate well with both the restoration of CQ accumulation and the level of CQ resensitization in CQR parasites.KEYWORDS: Malaria parasite, chloroquine resistance, chemosensitization, chlorpheniramine, PfCRT, Xenopus oocytes T he malaria parasite Plasmodium falciparum has proven largely refractory to the vaccine approaches trialled to date and reliance on chemotherapy is under serious threat with the recent emergence of parasites that are resistant to the current mainstay of malaria treatment (the artemisinin-based combination therapies).1 As a result, malaria remains a global health problem; there are around 225 million clinical cases and over 1.2 million deaths each year, 2 and the disease also imposes considerable socio-economic burdens upon afflicted countries. Chloroquine (CQ, Figure 1A) was a cheap, safe, and efficacious treatment for the disease until the eventual emergence and spread of resistant parasites. Resistance to CQ is caused primarily by mutations in the P. falciparum CQ resistance transporter, PfCRT.3 Within the P. falciparum-infected erythrocyte, PfCRT is found in the membrane of the parasite's digestive vacuole 4 (DV; pH 5−5.5); the organelle in which CQ accumulates and exerts its antimalarial effect. Mutations in PfCRT that confer CQ resistance result in a marked reduction in the accumulation of CQ within the DV. Using the Xenopus laevis oocyte expression system, a CQ resistance-conferring form of PfCRT (PfCRT CQR ) was shown to transport CQ, whereas the wild-type form found in CQ-sensitive (CQS) parasites (PfCRT CQS ) lacked this ability. 5Mutations in PfCRT have been associated with decreases or increases in the parasite's susceptibility to other antimalarials, 6 and the transporter has been shown to be one of the key determinants of the parasite's response to a diverse set of novel antiplasmodial compounds. 7 Whether these effects are due to PfCRT-mediated drug efflux and/or the inhibition of the transporter's normal function (which is essential for the survival of the parasite, but currently unknown) remains unclear.8 A better understanding of the interactions between PfCRT CQR and its substrates and inhibitors ...

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Chemical Genomic Profiling for Antimalarial Therapies, Response Signatures, and Molecular Targets

Cited by 131 publications

References 41 publications

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

Chlorpheniramine Analogues Reverse Chloroquine Resistance inPlasmodium falciparumby Inhibiting PfCRT

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