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
{"title":"A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria","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","doi":"10.1126/science.adm7966","DOIUrl":null,"url":null,"abstract":"<div >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 <i>Plasmodium falciparum</i> 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 <i>PfSec13</i>, 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.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":"385 6716","pages":""},"PeriodicalIF":45.8000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/science.adm7966","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
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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.
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