A Mitochondria-Penetrating Peptide Exerts Potent Anti-Plasmodium Activity and Localizes at Parasites' Mitochondria.

Sangdao Somsri,Ratchaneewan Aunpad,Natthaporn Klubthawee,Mathirut Mungthin,Warunee Hanpithakpong,Poom Adisakwattana

doi:10.3390/antibiotics10121560

Abstract

Mitochondria are considered a novel drug target as they play a key role in energy production and programmed cell death of eukaryotic cells. The mitochondria of malaria parasites differ from those of their vertebrate hosts, contributing to the drug selectivity and the development of antimalarial drugs. (Fxr)3, a mitochondria-penetrating peptide or MPP, entered malaria-infected red cells without disrupting the membrane and subsequently killed the blood stage of P. falciparum parasites. The effects were more potent on the late stages than on the younger stages. Confocal microscopy showed that the (Fxr)3 intensely localized at the parasite mitochondria. (Fxr)3 highly affected both the lab-strain, chloroquine-resistant K1, and freshly isolated malaria parasites. (Fxr)3 (1 ng/mL to 10 μg/mL) was rarely toxic towards various mammalian cells, i.e., mouse fibroblasts (L929), human leukocytes and erythrocytes. At a thousand times higher concentration (100 μg/mL) than that of the antimalarial activity, cytotoxicity and hemolytic activity of (Fxr)3 were observed. Compared with the known antimalarial drug, atovaquone, (Fxr)3 exhibited more rapid killing activity. This is the first report on antimalarial activity of (Fxr)3, showing localization at parasites’ mitochondria.

Highlights

Malaria remains a life-threatening disease, causing millions of cases worldwide with around 405,000 deaths annually [1]
mitochondriapenetrating peptides (MPPs) can target and penetrate the mitochondria of active eukaryotic cells by two major properties, being cationic and lipophilic. These characteristics may explain the antiplasmodial activity of our peptide
In order to exploit MPPs as antimalarial agents, they must be able to pass through the red blood cell membrane withcells by two major properties, being cationic and lipophilic

Summary

Introduction

Malaria remains a life-threatening disease, causing millions of cases worldwide with around 405,000 deaths annually [1]. There are five different species of the Plasmodium parasite causing human malaria, namely Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi. The increase and spread of multidrug-resistant P. falciparum have become major challenges to malaria treatment and are correlated with increases in morbidity and mortality in many malaria-endemic countries [1]. In response to this harsh predicament, artemisinin-based combination therapies (ACTs) have been recommended and widely established in malariaendemic regions. The recent Global Malaria Programme report pointed to artemisinin and ACT resistance causing significant delays in parasite clearance [3]. The development of novel antimalarial drugs and more effective therapy is urgently needed

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