2. Academic Validation
  3. A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria

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

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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