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

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.

Cell-Penetrating Antimicrobial Peptides with Anti-Infective Activity against Intracellular Pathogens

“…(Fxr)3 showed more potent antimalarial activity toward late-stage (trophozoite and schizont) parasites, consistent with the high intensity of (Fxr)3 localized in the parasites’ mitochondria observed by confocal microscopy. The antimalarial action may be related to a collapse of the mitochondrial membrane potential [ 70 ].…”

Bioactive Peptides against Human Apicomplexan Parasites

“…In addition to reducing parasitemia, some peptides are capable of modifying the immune response in the host by reducing the overproduction of proinflammatory cytokines and, as a consequence, modulating damage to organs that are severely affected, such as the liver [ 99 ].…”

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part IV. Plasmodium spp.

“…During the last years (2019-2022), several studies [14][15][16][17][18][19][20][21] were published discussing new approaches to identify novel drug targets for Plasmodium spp. Stanway et al [14] hypothesized that identifying genes encoding the high metabolic activities behind rapid development of a single sporozoite (invading the liver) into thousands of daughter-merozoites (invading RBCs) should reveal several potential drug targets.…”

“…The investigators observed (Fxr) 3 intensive localization in mitochondria of merozoites that entered the infected RBCs without membrane disruption with subsequent death of erythrocytic stages. Compared to atovaquone, (Fxr) 3 exhibited significant lethal effects on both freshly isolated, and laboratory cultured strains as well as a chloroquine-resistant strain, with minimum toxicity towards various mammalian cells [20] .…”