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Identification of antimalarial targets of chloroquine by a combined deconvolution strategy of ABPP and MS-CETSA 被引量:1
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作者 Peng Gao Yan-Qing Liu +17 位作者 Wei Xiao Fei Xia Jia-Yun Chen Li-Wei Gu Fan Yang Liu-Hai Zheng Jun-Zhe Zhang Qian Zhang Zhi-Jie Li Yu-Qing Meng Yong-Ping Zhu Huan Tang Qiao-Li Shi qiu-yan guo Ying Zhang Cheng-Chao Xu Ling-Yun Dai Ji-Gang Wang 《Military Medical Research》 SCIE CAS CSCD 2023年第1期64-77,共14页
Background: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine(CQ) has played an i... Background: Malaria is a devastating infectious disease that disproportionally threatens hundreds of millions of people in developing countries. In the history of anti-malaria campaign, chloroquine(CQ) has played an indispensable role, however, its mechanism of action(MoA) is not fully understood.Methods: We used the principle of photo-affinity labeling and click chemistry-based functionalization in the design of a CQ probe and developed a combined deconvolution strategy of activity-based protein profiling(ABPP) and mass spectrometry-coupled cellular thermal shift assay(MS-CETSA) that identified the protein targets of CQ in an unbiased manner in this study. The interactions between CQ and these identified potential protein hits were confirmed by biophysical and enzymatic assays.Results: We developed a novel clickable, photo-affinity chloroquine analog probe(CQP) which retains the antimalarial activity in the nanomole range, and identified a total of 40 proteins that specifically interacted and photocrosslinked with CQP which was inhibited in the presence of excess CQ. Using MS-CETSA, we identified 83 candidate interacting proteins out of a total of 3375 measured parasite proteins. At the same time, we identified 8 proteins as the most potential hits which were commonly identified by both methods.Conclusions: We found that CQ could disrupt glycolysis and energy metabolism of malarial parasites through direct binding with some of the key enzymes, a new mechanism that is different from its well-known inhibitory effect of hemozoin formation. This is the first report of identifying CQ antimalarial targets by a parallel usage of labeled(ABPP)and label-free(MS-CETSA) methods. 展开更多
关键词 CHLOROQUINE ANTIMALARIA Activity-based protein profiling(ABPP) Cellular thermal shift assay(CETSA) Quantitative proteomics
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Network Pharmacology-based Approaches Capture Essence of Chinese Herbal Medicines 被引量:93
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作者 Yan-qiong Zhang Xia Mao +2 位作者 qiu-yan guo Na Lin Shao Li 《Chinese Herbal Medicines》 CAS 2016年第2期107-116,共10页
Traditional Chinese Medicine(TCM), a crucial component of the current medical system, has been extensively used in clinical practice due to its valuable therapeutic efficacy, and its potentials as an important sourc... Traditional Chinese Medicine(TCM), a crucial component of the current medical system, has been extensively used in clinical practice due to its valuable therapeutic efficacy, and its potentials as an important source of new pharmacophores. TCM is characterized by holistic theory, which emphasizes maintaining the balance of the patient's whole body using herbal formulae(fangji in Chinese) composed of mixtures of herbs with multiple bioactive ingredients. Because of the complex nature of these formulae, it is necessary to develop systematic methods to identify their bioactive ingredients and to clarify their mechanisms of action. With the rapid progress in bioinformatics, systems biology, and polypharmacology, "network pharmacology", which shifts the "one target, one drug" paradigm to the "network target, multi-component" strategy, has attracted the attention because it can not only reveal the underlying complex interactions between a herbal formula and cellular proteins but detect the influence of their interactions on the function and behavior of the system. Growing evidence shows that the network pharmacology strategy can be a powerful approach to modern research on TCM. The present paper focuses on the basis of network pharmacology and the recent progress in its methodology, illustrates its utility in screening bioactive ingredients and elucidating the mechanisms of action of TCM herbal formulae, analyzes its limitations and problems, and discusses its development direction and application prospects. 展开更多
关键词 bioactive ingredient Chinese herbal medicine molecular mechanism network pharmacology network target
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