Abstract
Apicomplexan parasites, through their motor machinery, produce the required propulsive force critical for host cell-entry. The conserved components of this so-called glideosome machinery are myosin A and myosin A Tail Interacting Protein (MTIP). MTIP tethers myosin A to the inner membrane complex of the parasite through 20 amino acid-long C-terminal end of myosin A that makes direct contacts with MTIP, allowing the invasion of Plasmodium falciparum in erythrocytes. Here, we discovered through screening a peptide library, a de-novo peptide ZA1 that binds the myosin A tail domain. We demonstrated that ZA1 bound strongly to myosin A tail and was able to disrupt the native myosin A tail MTIP complex both in vitro and in vivo. We then showed that a shortened peptide derived from ZA1, named ZA1S, was able to bind myosin A and block parasite invasion. Overall, our study identified a novel anti-malarial peptide that could be used in combination with other antimalarials for blocking the invasion of Plasmodium falciparum.
Highlights
The burden caused by a malarial parasite—Plasmodium falciparum—remains huge despite a recent decline in the number of malaria cases [1]
This is accompanied by a rise in cytosolic Ca2+ levels, engagement of erythrocyte binding antigen 175 (EBA 175) with glycophorin A on red blood cell (RBC) [8], and formation of Rhoptry Neck Protein (RON) 2/4/5-Apical Membrane Antigen 1 (AMA1) complex [9,10,11]
The actinomysin motor is present in the inner membrane complex of the parasite and composed of actin, myosin A, myosin A tail interacting protein (MTIP), essential light chain (ELC), glideosome-associated proteins—GAP 40, 45, 50, and thrombosponding-related anonymous protein (TRAP)
Summary
The burden caused by a malarial parasite—Plasmodium falciparum—remains huge despite a recent decline in the number of malaria cases [1]. The encounter of the malarial parasite with host erythrocyte is mediated by sequential and highly dynamic processes involving initial interaction of the egressed merozoite, leading to re-orientation of the apical end, the formation of a tight junction in between the two membranes, followed by the engagement of invasion motor and entry. This is concluded by the shedding of a protein coat, the formation of the parasitophorous vacuole, resealing of red blood cell (RBC) membrane, and echinocytosis [2,3,4]. We discovered another peptide—ZA1S—from the original de novo peptide ZA1, but shorter in length, that was able to enter the parasite, bind Myosin A tail, and block invasion
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