Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis

Gao, Peng1; Wang, Jianyou2; Tang, Huan3,4; Pang, Huanhuan3,4; Liu, Jiemei1; Wang, Chen3,4; Xia, Fei3,4; Chen, Honglin2; Xu, Liting3,4; Zhang, Junzhe3,4; Yuan, Lixia5,6,7; Han, Guang2; Wang, Jigang2,3,4,8,9,10; Liu, Gang1

2024-02-20

10.1186/s12964-023-01409-5

CELL COMMUNICATION AND SIGNALING   影响因子和分区

1478-811X

BackgroundMalaria remains a global health burden, and the emergence and increasing spread of drug resistance to current antimalarials poses a major challenge to malaria control. There is an urgent need to find new drugs or strategies to alleviate this predicament. Celastrol (Cel) is an extensively studied natural bioactive compound that has shown potentially promising antimalarial activity, but its antimalarial mechanism remains largely elusive.MethodsWe first established the Plasmodium berghei ANKA-infected C57BL/6 mouse model and systematically evaluated the antimalarial effects of Cel in conjunction with in vitro culture of Plasmodium falciparum. The potential antimalarial targets of Cel were then identified using a Cel activity probe based on the activity-based protein profiling (ABPP) technology. Subsequently, the antimalarial mechanism was analyzed by integrating with proteomics and transcriptomics. The binding of Cel to the identified key target proteins was verified by a series of biochemical experiments and functional assays.ResultsThe results of the pharmacodynamic assay showed that Cel has favorable antimalarial activity both in vivo and in vitro. The ABPP-based target profiling showed that Cel can bind to a number of proteins in the parasite. Among the 31 identified potential target proteins of Cel, PfSpdsyn and PfEGF1-alpha were verified to be two critical target proteins, suggesting the role of Cel in interfering with the de novo synthesis of spermidine and proteins of the parasite, thus exerting its antimalarial effects.ConclusionsIn conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel.5LH6oqsCtKBdVDis1L_PeKVideo AbstractConclusionsIn conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel.5LH6oqsCtKBdVDis1L_PeKVideo Abstract

Celastrol Antimalarial Spermidine Protein synthesis

SCI

英语

通讯

Establishment of Sino-Austria "Belt and Road" Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research[2020YFE0205100] ; National Key Research and Development Program of China["2020YFA0908000","2022YFC2303600"] ; 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"] ; Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences["CI2021B014","CI2023D003"] ; China Postdoctoral Science Foundation[2022 M721541] ; Science and Technology Foundation of Shenzhen[JCYJ20210324115800001] ; Shenzhen Medical Research Fund of Shenzhen Medical Academy of Research and Translation[B2302051] ; Distinguished Expert Project of Sichuan Province Tianfu Scholar[CW202002] ; Fundamental Research Funds for the Central public welfare research institutes[ZZ13-ZD-07]

Cell Biology

Cell Biology

WOS:001169120200002

BMC

Web of Science

1.Southern Med Univ, Shunde Hosp, Dept Rehabil Med, Foshan 528300, Peoples R China
2.Henan Univ, Sch Pharm, State Key Lab Antiviral Drugs, Kaifeng 475004, Peoples R China
3.China Acad Chinese Med Sci, Artemisinin Res Ctr, State Key Lab Qual Ensurance & Sustainable Use Dao, Beijing 100700, Peoples R China
4.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China
5.Southern Med Univ, Sch Tradit Chinese Med, Guangzhou 510515, Peoples R China
6.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China
7.Southern Med Univ, Guangdong Prov Key Lab Chinese Med Pharmaceut, Guangzhou 510515, Peoples R China
8.Shenzhen Inst Resp Dis, Dept Pulm & Crit Care Med, Shenzhen 518020, Peoples R China
9.Shenzhen Peoples Hosp, Shenzhen Clin Res Ctr Geriatr, Shenzhen 518020, Peoples R China
10.Southern Univ Sci & Technol, Jinan Univ, Affiliated Hosp 1, Clin Med Coll 2, Shenzhen 518020, Peoples R China

Gao, Peng,Wang, Jianyou,Tang, Huan,et al. Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis[J]. CELL COMMUNICATION AND SIGNALING,2024,22(1).

Gao, Peng.,Wang, Jianyou.,Tang, Huan.,Pang, Huanhuan.,Liu, Jiemei.,...&Liu, Gang.(2024).Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis.CELL COMMUNICATION AND SIGNALING,22(1).

Gao, Peng,et al."Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis".CELL COMMUNICATION AND SIGNALING 22.1(2024).