A Kalihinol Analog Disrupts Apicoplast Function and Vesicular Trafficking in Malaria

Overview

Journal Science

Specialty Science

Date 2024 Sep 26

PMID 39325875

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

Affiliations

Soon will be listed here.

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 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 , 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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