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ACS Infect Dis. 2019 Dec 13;5(12):2076-2086. doi: 10.1021/acsinfecdis.9b00257. Epub 2019 Dec 2.

Ozonide Antimalarials Alkylate Heme in the Malaria Parasite Plasmodium falciparum.

Author information

1
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences , Monash University , 381 Royal Parade , Parkville , Victoria 3052 , Australia.
2
College of Pharmacy , University of Nebraska Medical Center , 986125 Nebraska Medical Center , Omaha , Nebraska 68198 , United States.
3
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences , Monash University , 381 Royal Parade , Parkville , Victoria 3052 , Australia.

Abstract

The mechanism of action of ozonide antimalarials involves activation by intraparasitic iron and the formation of highly reactive carbon-centered radicals that alkylate malaria parasite proteins. Given free intraparasitic heme is generally thought to be the iron source responsible for ozonide activation and its likely close proximity to the activated drug, we investigated heme as a possible molecular target of the ozonides. Using an extraction method optimized for solubilization of free heme, untargeted LC-MS analysis of ozonide-treated parasites identified several regioisomers of ozonide-alkylated heme, which resulted from covalent modification of the heme porphyrin ring by an ozonide-derived carbon-centered radical. In addition to the intact alkylated heme adduct, putative ozonide-alkylated heme degradation products were also detected. This study directly demonstrates ozonide modification of heme within the malaria parasite Plasmodium falciparum, revealing that this process may be important for the biological activity of ozonide antimalarials.

KEYWORDS:

Plasmodium falciparum; drug targets; heme; malaria; ozonide antimalarials; peroxides

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