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Amporndanai, Kangsa, Pinthong, Nattapon, O’Neill, Paul M., Hong, W. David, Amewu, Richard K., Pidathala, Chandrakala, Berry, Neil G., Leung, Suet C., Ward, Steve 
ORCID: https://orcid.org/0000-0003-2331-3192, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Hasnain, S. Samar and Antonyuk, Svetlana V.
(2022)
'Targeting the Ubiquinol-Reduction (Qi) Site of the Mitochondrial Cytochrome bc1 Complex for the Development of Next Generation Quinolone Antimalarials'. Biology, Vol 11, Issue 8, e1109.
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biology-11-01109.pdf - Published Version Available under License Creative Commons Attribution. Download (27MB) | Preview |
Abstract
Antimalarials targeting the ubiquinol-oxidation (Qo) site of the Plasmodium falciparum bc1 complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qo site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome bc1 complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for Plasmodial cytochrome bc1. Our crystallographic studies have enabled comparison of an in-silico homology docking model of P. falciparum with the mammalian’s equivalent, enabling an examination of how binding compares for the 2- versus 3-aryl analogues. Based on crystallographic and computational modeling, key differences in human and P. falciparum Qi sites have been mapped that provide new insights that can be exploited for the development of next-generation antimalarials with greater selective inhibitory activity against the parasite bc1 with improved antimalarial properties.
| Item Type: | Article |
|---|---|
| Subjects: | QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials QW Microbiology and Immunology > QW 45 Microbial drug resistance. General or not elsewhere classified. QX Parasitology > Protozoa > QX 135 Plasmodia |
| Faculty: Department: | Biological Sciences > Department of Tropical Disease Biology |
| Digital Object Identifer (DOI): | https://doi.org/10.3390/biology11081109 |
| Depositing User: | Marie Hatton |
| Date Deposited: | 17 Aug 2022 09:19 |
| Last Modified: | 17 Aug 2022 09:19 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/20915 |
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