A kalihinol analog disrupts apicoplast function and vesicular trafficking in <i>P. falciparum</i> malaria.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39325875.
- Also identified by DOI 10.1126/science.adm7966 and PMC identifier 11793105.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>Plasmodium falciparum</i> 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 <i>PfSec13</i>, 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.
Medical subject headings
- Antimalarials
- Apicoplasts
- Malaria, Falciparum
- Plasmodium falciparum
- Diterpenes