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

  • Science. 2024 Sep 27;385(6716):eadm7966. doi: 10.1126/science.adm7966.
Z Chahine  1 ,  S Abel  1 ,  T Hollin  1 ,  G L Barnes  2 ,  J H Chung  2 ,  M E Daub  2 ,  I Renard  3 ,  J Y Choi  3 ,  P Vydyam  3 ,  A Pal  3 ,  M Alba-Argomaniz  4  5  6 ,  C A S Banks  7 ,  J Kirkwood  8 ,  A Saraf  7  9 ,  I Camino  10 ,  P Castaneda  10 ,  M C Cuevas  10 ,  J De Mercado-Arnanz  10 ,  E Fernandez-Alvaro  10 ,  A Garcia-Perez  10 ,  N Ibarz  10 ,  S Viera-Morilla  10 ,  J Prudhomme  1 ,  C J Joyner  4  5  6 ,  A K Bei  11 ,  L Florens  7 ,  C Ben Mamoun  3 ,  C D Vanderwal  2  12 ,  K G Le Roch  1
Affiliations
  • 1. Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, USA.
  • 2. Department of Chemistry, University of California, Irvine, CA, USA.
  • 3. Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA.
  • 4. Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, USA.
  • 5. Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA.
  • 6. Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA.
  • 7. Stowers Institute for Medical Research, Kansas City, MO, USA.
  • 8. Metabolomics Core Facility, University of California, Riverside, CA, USA.
  • 9. Present address: Shankel Structural Biology Center, The University of Kansas, Lawrence, KS, USA.
  • 10. GSK, Tres Cantos (Madrid), Spain.
  • 11. Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.
  • 12. Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA.
PMID: 39325875 DOI: 10.1126/science.adm7966
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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