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Mode of action of synthetic antimalarial peroxides

Jourdan, Joëlle. Mode of action of synthetic antimalarial peroxides. 2017, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12651

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Abstract

Malaria is one of the most widespread infectious diseases which caused an estimated 212 million cases and 429,000 deaths worldwide in 2015. Today, artemisinin-based combination therapy (ACT), a combination of the fast-acting artemisinin with a longer lasting drug, is recommended to treat uncomplicated Plasmodium falciparum infections. Artemisinin is of highest antimalarial potency and selectivity. However, as a natural product, artemisinin and its derivatives also have drawbacks. In 2004 Jonathan Vennerstrom reported the development of synthetic peroxides that might overcome these shortcomings. A first-generation synthetic peroxide, OZ277, was registered with piperaquine for combination therapy in India in 2012 and the next-generation ozonide OZ439 is being tested in Phase IIb clinical trials in combination with piperaquine or ferroquine. The exact mode of action of synthetic peroxides and artemisinins, both thought to have similar modes of action, is not known. Recently, prolonged parasite clearance rates in patients after treatment with artesunate or ACTs were published, indicating a starting artemisinin resistance. Therefore, the fear of cross-resistance of artemisinin-resistant clinical isolates against OZ439, the leading candidate in the drug pipeline, overshadowed its superior properties.
In this PhD thesis the mode of action of synthetic peroxides was further elucidated. First, I used monoclonal antibodies raised against the adamantane-portion of ozonides to perform subcellular localization studies and to identify alkylation signatures in P. falciparum. Since it was not possible to identify the alkylated parasite proteins with antibodies, I set up a novel approach using click chemistry with newly synthesized alkyne derivatives of antimalarial peroxides. Further, the potential of cross-resistance by an artemisinin-resistant clinical isolate to OZ439 was tested.
I showed that alkylation of proteins by OZ277 and OZ439 takes place in the cytoplasm and other structures such as the nucleus and the food vacuole, in agreement with previous findings. Comparing the alkylation signatures of artemisinin and ozonides, I identified common targets to both drugs, such as the protein PFNF54_01699. Overall, the ozonides had a larger target space than artemisinin. In addition, we found, that there is no cross-resistance in vitro of an artemisinin-resistant clinical P. falciparum isolate to OZ439, indicating that OZ439 has the potential to circumvent artemisinin resistance. Nevertheless, larger clinical studies are needed to investigate if OZ439 is effective against artemisinin-resistant malarial parasites.
Advisors:Mäser, Pascal and Soldati-Favre, Dominique
Faculties and Departments:05 Faculty of Science
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Mäser, Pascal
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12651
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (VI, 123 Seiten)
Language:English
Identification Number:
Last Modified:21 Jun 2018 04:30
Deposited On:20 Jun 2018 12:15

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