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Journal article
Design, synthesis, and biological evaluation of multiple targeting antimalarials
Acta pharmaceutica Sinica. B, v 11(9), pp 2900-2913
Sep 2021
PMID: 34589403
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Malaria still threatens global health seriously today. While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors, multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance. Here, we performed a structure-based drug design on mitochondrial respiratory chain of Plasmodium falciparum and identified an extremely potent molecule, RYL-581, which binds to multiple protein binding sites of P. falciparum simultaneously (allosteric site of type II NADH dehydrogenase, Qo and Qi sites of cytochrome bc1). Antimalarials with such multiple targeting mechanism of action have never been reported before. RYL-581 kills various drug-resistant strains in vitro and shows good solubility as well as in vivo activity. This structure-based strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future, especially for drug discovery on membrane-associated targets.
A highly potent antimalarial compound, RYL-581, has a potential multi-targeting mechanism of action by simultaneously binding to three pockets (allosteric site of PfNDH2, Qo and Qi sites of Pfbc1). [Display omitted]
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Details
- Title
- Design, synthesis, and biological evaluation of multiple targeting antimalarials
- Creators
- Yiqing Yang - Tsinghua UniversityTongke Tang - Unit of Human Parasite Molecular and Cell Biology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, ChinaXiaolu Li - Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China.Thomas Michel - University of Paris-SaclayLiqin Ling - Drexel UniversityZhenghui Huang - Institut Pasteur of ShanghaiMaruthi Mulaka - Drexel UniversityYue Wu - Tsinghua UniversityHongying Gao - Tsinghua UniversityLiguo Wang - Tsinghua UniversityJing Zhou - West China Hospital of Sichuan UniversityBrigitte Meunier - University of Paris-SaclayHangjun Ke - Drexel UniversityLubin Jiang - Institut Pasteur of ShanghaiYu Rao - Tsinghua University
- Publication Details
- Acta pharmaceutica Sinica. B, v 11(9), pp 2900-2913
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000700583000005
- Scopus ID
- 2-s2.0-85108011176
- Other Identifier
- 991019169797204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy