acyclovir and Malaria--Falciparum

Infection by Plasmodium falciparum is the leading cause of malaria in humans. The parasite contains a unique and essential plastid-like organelle called the apicoplast that, similar to the mitochondria and chloroplast, houses its own genome that must undergo replication and repair. The putative apicoplast replicative DNA polymerase, POM1, has no direct orthologs in mammals, making the P. falciparum POM1 an attractive antimalarial drug target. Here, we report on a fluorescent high-throughput DNA polymerase assay that relies on the ability of POM1 to perform strand-displacement synthesis through the stem of a DNA hairpin substrate, thereby separating a Cy3 dye from a quencher. Assay-validation experiments were performed using 384-well plates and resulted in a signal window of 7.90 and aZ' factor of 0.71. A pilot screen of a 2880-compound library identified 62 possible inhibitors that cause more than 50% inhibition of polymerase activity. The simplicity and statistical robustness of the assay suggest it is well suited for the screening of novel apicoplast polymerase inhibitors that may serve as lead compounds in antimalarial drug-discovery efforts.

Topics: Antimalarials; Apicoplasts; Chloroplasts; DNA; DNA-Directed DNA Polymerase; Drug Discovery; Exonucleases; Humans; Kinetics; Malaria, Falciparum; Mitochondria; Multienzyme Complexes; Nucleic Acid Synthesis Inhibitors; Peptide Library; Plasmodium falciparum; Protozoan Proteins; Spectrometry, Fluorescence

Post-malaria neurological syndrome (PMNS) defined by a post-infective encephalopathy occurring within 2 months after an episode of Plasmodium falciparum infection is still a debated entity. We describe 2 cases of PMNS in 2 patients of African origin, born and living in France. Both patients had severe P. falciparum infection, followed by PMNS. They recovered with no sequelae. These are the first-reported cases of PMNS in patients of African ethnicity and living in France.

Topics: Acyclovir; Adolescent; Adult; Brain Diseases; Cote d'Ivoire; Encephalitis, Herpes Simplex; France; Gambia; Humans; Malaria, Falciparum; Male; Syndrome; Treatment Outcome