Antimalarial activity and mechanism of action determination of mitochondria-penetrating peptide : a key to increase antimalarial drug efficacy

Name: Saengdao Somsri

keyword: Antimalarial drug

; Malaria

; Mitochondria

; Mitochondria penetrating peptide

; Mechanism of action

Abstract: Mitochondrion is considered as a novel drug target as it plays a key role in energy production and programmed cell death of eukaryotic cells. The difference of mitochondria of malaria parasites from those of their vertebrate hosts contribute to the drug selectivity and might be a good target for antimalarial drug development. Mitochondria-penetrating peptide or MPP can pass through the red blood cell membrane without disruption or destruction and subsequently killed the blood stage malaria, P. falciparum. MPP showed more potent antimalarial activity toward late stage (trophozoite and schizont) parasite which is comparable to high intensity of MPP localized in parasites’ mitochondria observed by confocal microscopy. Moreover, MPP exhibited high antimalarial activity against chloroquine-resistant K1 strain of P. falciparum. MPP showed very low toxic toward normal mouse fibroblast L929 cells, human peripheral white blood cells (PBMCs) and red blood cells at the concentration from 1 ng/mL to 10 µg/mL. At the highest concentration of MPP (100 µg/mL), the (2) cytotoxicity and hemolytic activity were observed, however the concentration is around thousand times higher than that of antimalarial activity. The combination of atovaquone could significantly reduce the IC50 value of MPP in five isolates including standard strain (K1 and 3D7) and three field isolated strains (KY564, J1 and J8). The mechanism of MPP was confirmed by the localization and membrane potential determination experiments. It localized at the mitochondria of living malaria parasite and caused a complete loss or collapse of mitochondrial membrane potential in five out of seven strains of P. falciparum including chloroquine-resistant strain K1. As far as we aware, this is the first report on antimalarial activity of MPP by the disruption or collapse of parasites’ mitochondrial membrane potential.

Thammasat University. Thammasat University Library

Address: BANGKOK

Email: preserv@tu.ac.th

Name: Ratchaneewan Aunpad

Role: advisor

Name: Mathirut Mungthin

Role: co-advisor

Name: Poom Adisakwattana

Role: co-advisor

Name: Warunee Hanpithakpong

Role: co-advisor

Name: Markus Winterberg

Role: co-advisor

Created: 2021

Modified: 2568-05-08

Issued: 2025-04-06

วิทยานิพนธ์/Thesis

application/pdf

DOI: 10.14457/TU.the.2020.1485

eng

DegreeName: Doctor of Philosophy

Level: Doctoral Degree

Descipline: Biomedical Sciences

Grantor: Thammasat University

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