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The antimalarial compound ELQ ‐400 is an unusual inhibitor of the bc 1 complex, targeting both Q o and Q i sites
Author(s) -
Song Zehua,
Iorga Bogdan I.,
Mounkoro Pierre,
Fisher Nicholas,
Meunier Brigitte
Publication year - 2018
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13035
Subject(s) - atovaquone , stereochemistry , chemistry , biology , mutant , biochemistry , gene , malaria , plasmodium falciparum , immunology
Inhibitors of the mitochondrial respiratory chain cytochrome bc 1 complex, such as the antimalarial atovaquone and ELQ ‐300, and many well‐studied compounds, are classified as either Q o or Q i site inhibitors based on their site of action. Here, we investigated the site of action of ELQ ‐400 that showed an unusual behaviour, being effective against parasites resistant to the Q o site inhibitor atovaquone or to the Q i site inhibitor ELQ ‐300. Analysis of yeast mutants and comparison with atovaquone and other ELQ s strongly suggest that ELQ ‐400 targets both Q o and Q i sites. Dual site inhibition would be particularly efficient as it would lower the risk of acquired resistance. However, such compounds are seldom found, which could be explained by structural and mechanistic differences between the sites.