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Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum.

ABSTRACT: Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 modulators, could inhibit the replication of the pathogenic P. falciparum stages in human red blood cells. Nine compounds with IC(50) values from 30 nM to 1.6 micrOM were identified. Each compound also altered the ATPase activity of purified P. falciparum Hsp70 in single-turnover assays, although higher concentrations of agents were required than was necessary to inhibit P. falciparum replication. Varying effects of these compounds on Hsp70s from other organisms were also observed. Together, our data indicate that pyrimidinone-amides constitute a novel class of anti-malarial agents.

SUBMITTER: Chiang AN

PROVIDER: S-EPMC2775490 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum.

Chiang Annette N AN Valderramos Juan-Carlos JC Balachandran Raghavan R Chovatiya Raj J RJ Mead Brian P BP Schneider Corinne C Bell Samantha L SL Klein Michael G MG Huryn Donna M DM Chen Xiaojiang S XS Day Billy W BW Fidock David A DA Wipf Peter P Brodsky Jeffrey L JL

Bioorganic & medicinal chemistry 20090120 4

Plasmodium falciparum, the Apicomplexan parasite that is responsible for the most lethal forms of human malaria, is exposed to radically different environments and stress factors during its complex lifecycle. In any organism, Hsp70 chaperones are typically associated with tolerance to stress. We therefore reasoned that inhibition of P. falciparum Hsp70 chaperones would adversely affect parasite homeostasis. To test this hypothesis, we measured whether pyrimidinone-amides, a new class of Hsp70 mo ...[more]

PMID: 19195901

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Project description:BACKGROUND:Plasmodium falciparum shares its most recent common ancestor with parasites found in African apes; these species constitute the so-called Laverania clade. In this investigation, the evolutionary history of Plasmodium lineages found in chimpanzees (Pan troglodytes) was explored. METHODS:Here, the remainders of 74 blood samples collected as part of the chimpanzees' routine health examinations were studied. For all positive samples with parasite lineages belonging to the Laverania clade, the complete mitochondrial genome (mtDNA), the gene encoding dihydrofolate reductase-thymidylate synthase (dhfr-ts), the chloroquine resistance transporter (Pfcrt), the circumsporozoite protein (csp), merozoite surface protein 2 (msp2), and the DBL-1 domain from var2CSA were amplified, cloned, and sequenced. Other Plasmodium species were included in the mtDNA, dhfr-ts, and csp analyses. Phylogenetic and evolutionary genetic analyses were performed, including molecular clock analyses on the mtDNA. RESULTS/CONCLUSIONS:Nine chimpanzees were malaria positive (12.2%); four of those infections were identified as P. falciparum, two as a Plasmodium reichenowi-like parasite or Plasmodium sp., one as Plasmodium gaboni, and two as Plasmodium malariae. All P. falciparum isolates were resistant to chloroquine indicating that the chimpanzees acquired such infections from humans in recent times. Such findings, however, are not sufficient for implicating chimpanzees as an animal reservoir for P. falciparum.Timing estimates support that the Laverania clade has co-existed with hominids for a long-period of time. The proposed species P. gaboni, Plasmodium billbrayi, and Plasmodium billcollinsi are monophyletic groups supporting that they are indeed different species.An expanded CSP phylogeny is presented, including all the Laverania species and other malarial parasites. Contrasting with other Plasmodium, the Laverania csp exhibits great conservation at the central tandem repeat region. Msp2 and var2CSA, however, show extended recent polymorphism in P. falciparum that likely originated after the P. reichenowi-P. falciparum split. The accumulation of such diversity may indicate adaptation to the human host. These examples support the notion that comparative approaches among P. falciparum and its related species will be of great value in understanding the evolution of proteins that are important in parasite invasion of the human red blood cell, as well as those involved in malaria pathogenesis.

Dataset Information

Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum.

Publications

Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum.

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