1. A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria.
- Author
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Chahine Z, Abel S, Hollin T, Barnes GL, Chung JH, Daub ME, Renard I, Choi JY, Vydyam P, Pal A, Alba-Argomaniz M, Banks CAS, Kirkwood J, Saraf A, Camino I, Castaneda P, Cuevas MC, De Mercado-Arnanz J, Fernandez-Alvaro E, Garcia-Perez A, Ibarz N, Viera-Morilla S, Prudhomme J, Joyner CJ, Bei AK, Florens L, Ben Mamoun C, Vanderwal CD, and Le Roch KG
- Subjects
- Animals, Humans, Mice, Disease Models, Animal, Drug Resistance genetics, Mutation, Protozoan Proteins metabolism, Protozoan Proteins genetics, Antimalarials chemistry, Antimalarials pharmacology, Apicoplasts drug effects, Apicoplasts metabolism, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Plasmodium falciparum drug effects, Plasmodium falciparum genetics, Diterpenes chemistry, Diterpenes pharmacology
- Abstract
We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13 , which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.
- Published
- 2024
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