A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in <i>P. falciparum</i> Malaria.

ABSTRACT: Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P.

SUBMITTER: Chahine Z 

PROVIDER: S-EPMC10690269 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature