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Characterization of amicarbalide derivatives as new antimalarial compounds: Investigation of the mode of action and the mechanism of resistance

Duffey, Maëlle

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Despite the tremendous progress in the fight against malaria during the last two decades, it remains one of the most important infectious diseases worldwide, leading to approximately 500 000 lethal cases annually, mostly among young children. The emergence and spread of resistance of the Plasmodium parasites to all the drugs currently available on the market are a major threat to its control and eradication. It moreover emphasizes the dire need for new antimalarial agents with distinct modes of action. Previously, the medicinal chemistry team at the biotechnology company 4SC AG, Munich, presented a series of promising antimalarial compounds, optimized around an amicarbalide backbone. Two agents were selected out of this series as lead-compounds for further studies, namely SC81458 and SC83288. The work presented here aims to characterize the in vitro activity of the SC-lead compounds. First, it revealed them as potent inhibitors of P. falciparum blood stage parasites, acting preferentially on late stages. The lack of activity on the ring stages is reflected in their fast speed of action, yet not as fast as artemisinin, the fastest compound described so far, that acts on all blood stages. Importantly, the SC-lead compounds were unaffected by the most common resistance mechanisms to antimalarial drugs used in the clinic. Particularly, no cross-resistance mechanism between artemisinin and its derivatives and the SC-lead compounds was observed, and their antiplasmodial modes of action appeared to be distinct from each other. The second part of this work focused on the mode of action of the SC-lead compounds and the mechanisms of resistance that the parasite could develop. Although the Ca2+ ATPase pump PfATP6 was disproved as a direct molecular target of the SC-lead compounds, it was demonstrated to be implicated in a resistance mechanism. The F972Y mutation and the overexpression of the A108T, A109T variant led to a drastic decrease in the SC-lead compounds responsiveness. The F972Y substitution correlated with an in vitro fitness cost for the parasite, which was linked to a lower intracellular calcium resting concentration compared to its parental line. The molecular details of the disturbed calcium homeostasis and its correlation with the resistance to the SC-lead compounds remain to be unraveled. Overall, the findings of this work demonstrate the promising in vitro potency of the SC-lead compounds, particularly SC83288, and highly support its further development into (pre)clinical trials.

Item Type: Dissertation
Supervisor: Lanzer, Prof. Dr. Michael
Date of thesis defense: 6 April 2018
Date Deposited: 19 Apr 2018 08:57
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Medizinische Fakultät Heidelberg > Department for Infectiology
Subjects: 000 Generalities, Science
500 Natural sciences and mathematics
570 Life sciences
Controlled Keywords: Plasmodium falciparum, antimalalrial drugs
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