Dataset Information

Development of Chemical Entities Endowed with Potent Fast-Killing Properties against Plasmodium falciparum Malaria Parasites.

ABSTRACT: One of the attractive properties of artemisinins is their extremely fast-killing capability, quickly relieving malaria symptoms. Nevertheless, the unique benefits of these medicines are now compromised by the prolonged parasite clearance times and the increasing frequency of treatment failures, attributed to the increased tolerance of Plasmodium falciparum to artemisinin. This emerging artemisinin resistance threatens to undermine the effectiveness of antimalarial combination therapies. Herein, we describe the medicinal chemistry efforts focused on a cGMP-dependent protein kinase (PKG) inhibitor scaffold, leading to the identification of novel chemical entities with very potent, similar to artemisinins, fast-killing potency against asexual blood stages that cause disease, and activity against gametocyte activation that is required for transmission. Furthermore, we confirm that selective PKG inhibitors have a slow speed of kill, while chemoproteomic analysis suggests for the first time serine/arginine protein kinase 2 (SRPK2) targeting as a novel strategy for developing antimalarial compounds with extremely fast-killing properties.

SUBMITTER: Matralis AN

PROVIDER: S-EPMC6816013 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Development of Chemical Entities Endowed with Potent Fast-Killing Properties against <i>Plasmodium falciparum</i> Malaria Parasites.

Matralis Alexios N AN Malik Adnan A Penzo Maria M Moreno Inmaculada I Almela Maria J MJ Camino Isabel I Crespo Benigno B Saadeddin Anas A Ghidelli-Disse Sonja S Rueda Lourdes L Calderon Felix F Osborne Simon A SA Drewes Gerard G Böesche Markus M Fernández-Álvaro Elena E Martin Hernando Jose Ignacio JI Baker David A DA

Journal of medicinal chemistry 20191014 20

One of the attractive properties of artemisinins is their extremely fast-killing capability, quickly relieving malaria symptoms. Nevertheless, the unique benefits of these medicines are now compromised by the prolonged parasite clearance times and the increasing frequency of treatment failures, attributed to the increased tolerance of <i>Plasmodium falciparum</i> to artemisinin. This emerging artemisinin resistance threatens to undermine the effectiveness of antimalarial combination therapies. H ...[more]

PMID: 31566384

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Project description:Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86 k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87-0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima's D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and association analyses, and supporting global surveillance for drug resistance markers and candidate vaccine antigens.

Dataset Information

Development of Chemical Entities Endowed with Potent Fast-Killing Properties against Plasmodium falciparum Malaria Parasites.

Publications

Development of Chemical Entities Endowed with Potent Fast-Killing Properties against <i>Plasmodium falciparum</i> Malaria Parasites.

Similar Datasets

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