Identification of antimalarial targets of chloroquine by a combined deconvolution strategy of ABPP and MS-CETSA
Identification of antimalarial targets of chloroquine by a combined deconvolution strategy of ABPP and MS-CETSA作者机构：Artemisinin Research CenterInstitute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing 100700China Department of Traditional Chinese MedicineSouthern Medical UniversityGuangzhou 510515China Department of Geriatricsthe Second Clinical Medical College of Jinan Universitythe First Affiliated Hospital of Southern University of Science and TechnologyShenzhen People’s HospitalShenzhen 518020GuangdongChina Institute of Molecular and Cell BiologyAgency for ScienceTechnology and Research(A*STAR)Singapore 138673Singapore Department of Biological SciencesNational University of SingaporeSinga‑pore 117543Singapore
出 版 物：《Military Medical Research》 (军事医学研究（英文版）)
年 卷 期：2023年第10卷第1期
页 面：64-77页
核心收录：
学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学]
基 金：suppor ted by the National Key Research and Development Program of China(2020YFA0908000) the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-C-202002) the National Natural Science Foundation of China(82074098,82003814) the CACMS Innovation Fund(CI2021A05101) the Fundamental Research Funds for the Central public welfare research institutes(ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-ND-010,ZZ15-ND-10 and ZZ14-FL-002)
主 题：Chloroquine Antimalaria Activity-based protein profiling(ABPP) Cellular thermal shift assay(CETSA) Quantitative proteomics
摘 要：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 ***: 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 ***: 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 ***: 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.
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