A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria
Year: 2024
Type: article
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.
Source: Science
Authors: Z. Chahine, S. Abel, T. Hollin, G. L. Barnes, J. H. Chung, M. E. Daub, I. Renard, J. Y. Choi, P. Vydyam, A. Pal, M. Alba-Argomaniz, C. A. S. Banks, J. Kirkwood, A. Saraf, I. Camino, P. Castaneda, M. C. Cuevas, J. De Mercado-Arnanz, E. Fernandez-Alvaro, A. Garcia-Perez, N. Ibarz, S. Viera-Morilla, J. Prudhomme, C. J. Joyner, A. K. Bei, L. Florens, C. Ben Mamoun, C. D. Vanderwal, K. G. Le Roch
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Bill and Melinda Gates Foundation, Emory University, Global Lyme Alliance, Steven and Alexandra Cohen Foundation, National Institutes of Health, National Institute of Food and Agriculture, University of California, San Diego, National Institute of Allergy and Infectious Diseases, Fogarty International Center, National Center for Advancing Translational Sciences, Office of Research Infrastructure Programs, National Institutes of Health
Awards: G1044130170, G141904343, G1476237564, Employing Genetic and Genomic Surveillance to Reveal Mechanisms of Malaria Parasite Persistance, G173225386, G1844053406, G278379982, G2971651979, G3251738510, Illumina NovaSeq 6000 Sequencing System, G3620708242, G4354717817, Antigen Discovery and Vaccine Development for Human Babesia Parasites, G4885028645, Hit-to-Lead Development of the Kalihinol Scaffold for Malaria Treatment, G5770243299, G6019734394, G6960408705, University of Georgia Research Foundation, Inc. - to support drug and vaccine development targeting vivax malaria that disproportionally affecting women and children in LIMC, G9000112919, G9000118633, G9000142254, G9000227440, G9000263072, Fosinopril analogs for the treatment of human babesiosis, Yale Clinical and Translational Science Award
OpenAlex ID: W4402891827