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. 2024 Sep 27;385(6716):eadm7966.
doi: 10.1126/science.adm7966. Epub 2024 Sep 27.

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

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

Z Chahine et al. Science. .

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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Conflict of interest statement

Competing interests: The following authors own shares in GlaxoSmithKline: E.F.-A., S.V.-M., A.G.-P., and P.C. All other authors declare that they have no competing interests or conflicts of interest. Correspondence and requests for materials should be addressed to K.G.L.R.

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