Understanding artemisinin compounds mode of action in killing Plasmodium falciparum by using mass spectrometry cellular thermal shift assay

• Main Author: Go, Ka Diam
• Other Authors: Zbynek Bozdech
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2023
• Subjects: Science::Biological sciences::Microbiology::Microorganisms
• Online Access: https://hdl.handle.net/10356/170075
• Institution: Nanyang Technological University

Plasmodium falciparum (Pf) is a lethal cause of malaria, which is a global health burden with an estimated 627 thousand deaths during 2020. Dihydroartemisinin (DHA)-piperaquine is one form of artemisinin-combination therapies (ACTs) used as a first-line antimalarial drug. Previous studies showed that a certain number of Pf40S and Pf60S ribosomal subunits as potential molecular targets of artemisinin and its derivatives. In this study, mass spectrometry cellular thermal shift assay isothermal dose response (MS-CETSAITDR) method was used to find out that up to 66 ribosomal subunits of Pf80S ribosome complex were thermal stabilized upon 1-hour treatment with either DHA or artemisinin or artesunate or artemether. Further cryoEM study confirmed the increase of PfRACK1 bound to Pf80S ribosome complex, that might cause significant thermal stabilization upon DHA treatment. Moreover, the results of MS-CETSAITDR also suggested that artemisinin, artesunate, artemether, and DHA significantly thermal stabilized Pf26S proteasome, T-complex protein 1 (PfTCP1), and redox metabolism proteins