sj733 and Malaria--Falciparum

SJ733, a newly developed inhibitor of P. falciparum ATP4, has a favorable safety profile and rapid antiparasitic effect but insufficient duration to deliver a single-dose cure of malaria. We investigated the safety, tolerability, and pharmacokinetics of a multidose SJ733 regimen and a single-dose pharmacoboost approach using cobicistat to inhibit CYP3A4, thereby increasing exposure.. Two multidose unboosted cohorts (n = 9) (SJ733, 300 mg and 600 mg daily for 3 days) followed by three single-dose boosted cohorts combining SJ733 (n = 18) (75-, 300-, or 600-mg single dose) with cobicistat (150-mg single dose) as a pharmacokinetic booster were evaluated in healthy volunteers (ClinicalTrials.gov: NCT02661373).. The multidose and pharmacoboosted approaches to delivering SJ733 were well-tolerated and significantly increased drug exposure and prediction of cure. This study supports the further development of SJ733 and demonstrates an innovative pharmacoboost approach for an antimalarial.. Global Health Innovative Technology Fund, Medicines for Malaria Venture, National Institutes of Health, and American Lebanese Syrian Associated Charities.

Topics: Antimalarials; Cobicistat; Folic Acid Antagonists; Heterocyclic Compounds, 4 or More Rings; Humans; Isoquinolines; Malaria; Malaria, Falciparum; Plasmodium falciparum

The emergence of Plasmodium falciparum resistance to frontline antimalarials, including artemisinin combination therapies, highlights the need for new molecules that act via novel mechanisms of action. Herein, we report the design, synthesis and antimalarial activity of a series of 2-aminobenzimidazoles, featuring a phenol moiety that is crucial to the pharmacophore. Two potent molecules exhibited IC

Topics: Antimalarials; Benzimidazoles; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Humans; Malaria, Falciparum; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship

Topics: Acrylamides; Adamantane; Adult; Alanine Transaminase; Aminopyridines; Aminoquinolines; Antimalarials; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Erythrocyte Transfusion; Erythrocytes; Female; Ferrous Compounds; Healthy Volunteers; Heterocyclic Compounds, 4 or More Rings; Humans; Indoles; Isoquinolines; Malaria, Falciparum; Male; Metallocenes; Parasitemia; Peroxides; Piperazines; Plasmodium falciparum; Primaquine; Pyrimidines; Quinolines; Spiro Compounds; Sulfones; Triazoles; Young Adult

The CRISPR/Cas9 system is a powerful genome editing technique employed in a wide variety of organisms including recently the human malaria parasite, P. falciparum. Here we report on further improvements to the CRISPR/Cas9 transfection constructs and selection protocol to more rapidly modify the P. falciparum genome and to introduce transgenes into the parasite genome without the inclusion of drug-selectable marker genes. This method was used to stably integrate the gene encoding GFP into the P. falciparum genome under the control of promoters of three different Plasmodium genes (calmodulin, gapdh and hsp70). These genes were selected as they are highly transcribed in blood stages. We show that the three reporter parasite lines generated in this study (GFP@cam, GFP@gapdh and GFP@hsp70) have in vitro blood stage growth kinetics and drug-sensitivity profiles comparable to the parental P. falciparum (NF54) wild-type line. Both asexual and sexual blood stages of the three reporter lines expressed GFP-fluorescence with GFP@hsp70 having the highest fluorescent intensity in schizont stages as shown by flow cytometry analysis of GFP-fluorescence intensity. The improved CRISPR/Cas9 constructs/protocol will aid in the rapid generation of transgenic and modified P. falciparum parasites, including those expressing different reporters proteins under different (stage specific) promoters.

Topics: Antimalarials; Clustered Regularly Interspaced Short Palindromic Repeats; Drug Resistance; Gene Editing; Genome, Protozoan; Heterocyclic Compounds, 4 or More Rings; Humans; Isoquinolines; Malaria, Falciparum; Mutation; Plasmodium falciparum