The antimalarial compound ELQ-400 is an unusual inhibitor of the bc1 complex, targeting both Qo and Qi sites

Zehua Song; Bogdan I Iorga; Pierre Mounkoro; Nicholas Fisher; Brigitte Meunier

doi:10.1002/1873-3468.13035

The antimalarial compound ELQ-400 is an unusual inhibitor of the bc₁ complex, targeting both Q_o and Q_i sites

FEBS Lett. 2018 Apr;592(8):1346-1356. doi: 10.1002/1873-3468.13035. Epub 2018 Mar 26.

Authors

Zehua Song^{1

2}, Bogdan I Iorga³, Pierre Mounkoro², Nicholas Fisher⁴, Brigitte Meunier²

Affiliations

¹ Translational Research Institute, Henan Provincial People's Hospital, School of Medicine, Henan University, Zhengzhou, China.
² Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
³ Institut de Chimie des Substances Naturelles, CNRS, UPR 2301, Labex LERMIT, Université Paris-Saclay, Gif-sur-Yvette, France.
⁴ MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI, USA.

PMID: 29574797
DOI: 10.1002/1873-3468.13035

Abstract

Inhibitors of the mitochondrial respiratory chain cytochrome bc₁ 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 ELQs 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.

Keywords: Qo and Qi site inhibitors; complex III; respiratory chain.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antimalarials / chemistry*
Electron Transport Complex III* / antagonists & inhibitors
Electron Transport Complex III* / chemistry
Enzyme Inhibitors / chemistry*
Molecular Docking Simulation*
Phenyl Ethers / chemistry*
Quinolones / chemistry*
Saccharomyces cerevisiae / enzymology*
Saccharomyces cerevisiae Proteins* / antagonists & inhibitors
Saccharomyces cerevisiae Proteins* / chemistry

Substances

Antimalarials
ELQ-400
Enzyme Inhibitors
Phenyl Ethers
Quinolones
Saccharomyces cerevisiae Proteins
Electron Transport Complex III

Associated data

PDB/4D6T
PDB/2A06