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A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria.
- Source :
-
Science (New York, N.Y.) [Science] 2024 Sep 27; Vol. 385 (6716), pp. eadm7966. Date of Electronic Publication: 2024 Sep 27. - Publication Year :
- 2024
-
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.
- Subjects :
- Animals
Humans
Mice
Disease Models, Animal
Drug Resistance genetics
Mutation
Protozoan Proteins metabolism
Protozoan Proteins genetics
Antimalarials chemistry
Antimalarials pharmacology
Apicoplasts drug effects
Apicoplasts metabolism
Malaria, Falciparum drug therapy
Malaria, Falciparum parasitology
Plasmodium falciparum drug effects
Plasmodium falciparum genetics
Diterpenes chemistry
Diterpenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 385
- Issue :
- 6716
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 39325875
- Full Text :
- https://doi.org/10.1126/science.adm7966