Design,synthesis, and biological evaluation of multiple targeting antimalarials |
| |
| Authors: | Yiqing Yang Tongke Tang Xiaolu Li Thomas Michel Liqin Ling Zhenghui Huang Maruthi Mulaka Yue Wu Hongying Gao Liguo Wang Jing Zhou Brigitte Meunier Hangjun Ke Lubin Jiang Yu Rao |
| |
| Affiliation: | 1. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China;2. 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, China;3. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China;4. 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;5. Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, Gif-sur-Yvette 91198, France;6. Center for Molecular Parasitology, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA;7. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China;8. The Nanjing Unicorn Academy of Innovation, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Nanjing 211135, China |
| |
| 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. |
| |
| Keywords: | Drug design Multiple targeting compounds Antimalarial inhibitors Mechanism of action Membrane proteins |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
