A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria

• 成果类型: Article
• 署名作者: Chahine, Z.; Abel, S.; Hollin, T.; Barnes, G. L.; Chung, J. H.; Daub, M. E.; Renard, I.; Choi, J. Y.; Vydyam, P.; Pal, A.; Alba-Argomaniz, M.; Banks, C. A. S.; Kirkwood, J.; Saraf, A.; Camino, I.; Castaneda, P.; Cuevas, M. C.; De Mercado-Arnanz, J.; Fernandez-Alvaro, E.; Garcia-Perez, A.; Ibarz, N.; Viera-Morilla, S.; Prudhomme, J.; Joyner, C. J.; Bei, A. K.; Florens, L.; Ben Mamoun, C.; Vanderwal, C. D.; Le Roch, K. G.
• 署名单位: University of California System; University of California Riverside; University of California System; University of California Irvine; Yale University; University System of Georgia; University of Georgia; University System of Georgia; University of Georgia; University System of Georgia; University of Georgia; Stowers Institute for Medical Research; University of California System; University of California Riverside; GlaxoSmithKline; Yale University; University of California System; University of California Irvine
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12435
• DOI: 10.1126/science.adm7966
• 发表日期: 2024-09-27
• 关键词: parasite plasmodium-falciparum; pyruvate-dehydrogenase complex; antimalarial activity; protein; artemisinin; label; resistance; PATHWAY; identification; biosynthesis

摘要

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.