Understanding artemisinin compounds mode of action in killing Plasmodium falciparum by using mass spectrometry cellular thermal shift assay
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 show...
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| Format: | Thesis-Doctor of Philosophy |
| Language: | English |
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Nanyang Technological University
2023
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| Online Access: | https://hdl.handle.net/10356/170075 |
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| Institution: | Nanyang Technological University |
| Language: | English |
| Summary: | 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 |
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