A kalihinol analog disrupts apicoplast function and vesicular trafficking in <i>P. falciparum</i> malaria
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.
Authors
- Zeinab Chahine (ORCID: https://orcid.org/0000-0001-8208-5869)
- Chester J. Joyner (ORCID: https://orcid.org/0000-0003-1367-2829)
- Choukri Ben Mamoun (ORCID: https://orcid.org/0000-0001-5028-1400)
- Pratap Vydyam (ORCID: https://orcid.org/0000-0003-4944-6006)
- Mauro Cuevas (ORCID: https://orcid.org/0000-0001-6180-4553)
- Christopher D. Vanderwal (ORCID: https://orcid.org/0000-0001-7218-4521)
- Mary Elisabeth Daub (ORCID: https://orcid.org/0000-0002-1368-9607)
- Isaline Renard (ORCID: https://orcid.org/0000-0003-4121-143X)
- Karine G. Le Roch (ORCID: https://orcid.org/0000-0002-4862-9292)
- Steffen Abel (ORCID: https://orcid.org/0000-0001-7769-4301)
- Anasuya Pal (ORCID: https://orcid.org/0000-0002-0068-8912)
- Isabel Camino (ORCID: https://orcid.org/0009-0005-4024-6894)
- Jae‐Yeon Choi (ORCID: https://orcid.org/0000-0002-9853-0987)
- Amy K. Bei (ORCID: https://orcid.org/0000-0003-1159-760X)
- Jing-Gung Chung (ORCID: https://orcid.org/0000-0001-8665-9348)
- Griffin L. Barnes (ORCID: https://orcid.org/0000-0002-5731-4380)
- Laurence Florens (ORCID: https://orcid.org/0000-0002-9310-6650)
- Jacques Prudhomme (ORCID: https://orcid.org/0000-0002-6161-5194)
- Thomas Hollin (ORCID: https://orcid.org/0000-0002-8089-3253)
- Nuria Ibarz (ORCID: https://orcid.org/0009-0008-3392-4812)
- Charles A.S. Banks (ORCID: https://orcid.org/0000-0002-0404-2940)
- M. Alba-Argomaniz (ORCID: https://orcid.org/0009-0008-0505-9390)
- Anita Saraf (ORCID: https://orcid.org/0000-0001-6756-0975)
- Jay S. Kirkwood (ORCID: https://orcid.org/0000-0002-5679-3500)
- E. Fernandez-Alvaro
- J. De Mercado-Arnanz
- P. Castaneda
- S. Viera-Morilla
- A. García-Pérez
Institutions
- University of California, Riverside (US)
- Stowers Institute for Medical Research (US)
- University of Kansas (US)
- University of Georgia (US)
- University of California, Irvine (US)
- Yale University (US)
- GlaxoSmithKline (Spain) (ES)
- GMV Innovating Solutions (Spain) (ES)
Publication Details
- Journal
- Science
- Published
- 2024-09-26
- DOI
- https://doi.org/10.1126/science.adm7966
- Citations
- 10
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 5.43
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
- Office of Research Infrastructure Programs, National Institutes of Health