Photoaffinity probe-based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum

Gao, Peng1,2,3; Wang, Jianyou4; Qiu, Chong1; Zhang, Huimin5; Wang, Chen1; Zhang, Ying1; Sun, Peng1; Chen, Honglin4; Wong, Yin Kwan1; Chen, Jiayun1; Zhang, Junzhe1; Tang, Huan1; Shi, Qiaoli1; Zhu, Yongping1; Shen, Shengnan1; Han, Guang4; Xu, Chengchao1,2,3; Dai, Lingyun2,3; Wang, Jigang1,2,3,4,5

2024-04-01

10.1002/imt2.176

IMETA   影响因子和分区

2770-5986

2770-596X

Malaria continues to pose a serious global health threat, and artemisinin remains the core drug for global malaria control. However, the situation of malaria resistance has become increasingly severe due to the emergence and spread of artemisinin resistance. In recent years, significant progress has been made in understanding the mechanism of action (MoA) of artemisinin. Prior research on the MoA of artemisinin mainly focused on covalently bound targets that are alkylated by artemisinin-free radicals. However, less attention has been given to the reversible noncovalent binding targets, and there is a paucity of information regarding artemisinin targets at different life cycle stages of the parasite. In this study, we identified the protein targets of artemisinin at different stages of the parasite's intraerythrocytic developmental cycle using a photoaffinity probe. Our findings demonstrate that artemisinin interacts with parasite proteins in vivo through both covalent and noncovalent modes. Extensive mechanistic studies were then conducted by integrating target validation, phenotypic studies, and untargeted metabolomics. The results suggest that protein synthesis, glycolysis, and oxidative homeostasis are critically involved in the antimalarial activities of artemisinin. In summary, this study provides fresh insights into the mechanisms underlying artemisinin's antimalarial effects and its protein targets.

antimalarial artemisinin chemical proteomics intraerythrocytic cycle photoaffinity probe

ESCI

英语

通讯

Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences["CI2023D003","CI2021B014"] ; China Academy of Chinese Medical Sciences (CACMS) Innovation Fund["CI2023E002","CI2021A05104","CI2021A05101"] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-C-202002] ; National Natural Science Foundation of China["82141001","82274182","82074098","82304577","82003814"] ; China Postdoctoral Science Foundation[2022M721541] ; Excellent Scientific and Technological Innovation Training Program of Shenzhen[RCYX20210706092040048] ; Shenzhen Science and Technology Innovation Commission["JCYJ20210324115800001","JCYJ20210324114014039","202228029"] ; Fundamental Research Funds for the Central Public Welfare Research Institutes["ZZ14-YQ-050","ZZ14-YQ-051","ZZ14-YQ-052","ZZ14-ND-010","ZZ15-ND-10","ZZ14-FL-002","ZZ14-YQ-059","ZZ16-ND-10-23","ZZ15-YQ-063"] ; Shenzhen Medical Research Fund of Shenzhen Medical Academy of Research[B2302051] ; Distinguished Expert Project of Sichuan Province Tianfu Scholar[CW202002] ; null[2023YFC3503900] ; null[2020YFA0908000] ; null[2022YFC2303603]

Microbiology

Microbiology

WOS:001165221700001

WILEY

Web of Science

1.China Acad Chinese Med Sci, Inst Chinese Mat Med, Artemisinin Res Ctr, State Key Lab Qual Ensurance & Sustainable Use Dao, Beijing, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen Inst Resp Dis, Dept Pulm & Crit Care Med, Shenzhen, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Shenzhen Clin Res Ctr Geriatr, Shenzhen, Peoples R China
4.Henan Univ, Sch Pharm, State Key Lab Antiviral Drugs, Kaifeng, Peoples R China
5.Shandong Acad Chinese Med, Jinan, Peoples R China

Gao, Peng,Wang, Jianyou,Qiu, Chong,et al. Photoaffinity probe-based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum[J]. IMETA,2024,3(2).

Gao, Peng.,Wang, Jianyou.,Qiu, Chong.,Zhang, Huimin.,Wang, Chen.,...&Wang, Jigang.(2024).Photoaffinity probe-based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum.IMETA,3(2).

Gao, Peng,et al."Photoaffinity probe-based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum".IMETA 3.2(2024).