Preclinical Antimalarial Combination Study of M5717, a Plasmodium falciparum Elongation Factor 2 Inhibitor, and Pyronaridine, a Hemozoin Formation Inhibitor
Matthias Rottmann, Brian Jonat, Christin Gumpp, Satish K. Dhingra, Marla J. Giddins, Xiaoyan Yin, Lassina Badolo, Béatrice Gréco, David A. Fidock, Claude Oeuvray, Thomas Spangenberg
Abstract
severe combined immunodeficient (SCID) mouse model. We also analyzed pharmacokinetic and pharmacodynamic parameters, including genomic sequencing of recrudescent parasites. We observed no pharmacokinetic interactions with the combination of M5717 and pyronaridine. M5717 did not negatively impact the rate of kill of the faster-acting pyronaridine, and the latter was able to suppress the selection of M5717-resistant mutants, as well as significantly delay the recrudescence of parasites both with suboptimal and optimal dosing regimens.
Topics & Concepts
HemozoinPlasmodium falciparumPharmacologyMalariaElongation factorMedicineChemistryImmunologyBiochemistryRibosomeGeneRNAMalaria Research and ControlComputational Drug Discovery MethodsDrug-Induced Hepatotoxicity and Protection