title: Design and evaluation of antimalarial peptides derived from prediction of short linear motifs in proteins related to erythrocyte invasion.
abstract: The purpose of this study was to investigate the blood stage of the malaria causing parasite, Plasmodium falciparum, to predict potential protein interactions between the parasite merozoite and the host erythrocyte and design peptides that could interrupt these predicted interactions. We screened the P. falciparum and human proteomes for computationally predicted short linear motifs (SLiMs) in cytoplasmic portions of transmembrane proteins that could play roles in the invasion of the erythrocyte by the merozoite, an essential step in malarial pathogenesis. We tested thirteen peptides predicted to contain SLiMs, twelve of them palmitoylated to enhance membrane targeting, and found three that blocked parasite growth in culture by inhibiting the initiation of new infections in erythrocytes. Scrambled peptides for two of the most promising peptides suggested that their activity may be reflective of amino acid properties, in particular, positive charge. However, one peptide showed effects which were stronger than those of scrambled peptides. This was derived from human red blood cell glycophorin-B. We concluded that proteome-wide computational screening of the intracellular regions of both host and pathogen adhesion proteins provides potential lead peptides for the development of anti-malarial compounds.
authors.affiliation: Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland; Complex and Adaptive Systems Laboratory, University College Dublin, Dublin, Ireland; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Department of Microbiology, School of Genetics and Microbiology, Moyne Institute of Preventive Medicine, Trinity College, Dublin, Ireland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bianchin
authors.affiliation: Department of Microbiology, School of Genetics and Microbiology, Moyne Institute of Preventive Medicine, Trinity College, Dublin, Ireland.
authors.forename: Angus
authors.initials: A
authors.lastname: Bell
authors.affiliation: Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland; Complex and Adaptive Systems Laboratory, University College Dublin, Dublin, Ireland; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Chubb
authors.affiliation: School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Doolan
authors.affiliation: Department of Microbiology, School of Genetics and Microbiology, Moyne Institute of Preventive Medicine, Trinity College, Dublin, Ireland.
authors.forename: Darren
authors.initials: D
authors.lastname: Leneghan
authors.affiliation: Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland; Complex and Adaptive Systems Laboratory, University College Dublin, Dublin, Ireland; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Ilias
authors.initials: I
authors.lastname: Stavropoulos
authors.affiliation: Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland; Complex and Adaptive Systems Laboratory, University College Dublin, Dublin, Ireland; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Shields
authors.affiliation: Conway Institute of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland; Complex and Adaptive Systems Laboratory, University College Dublin, Dublin, Ireland; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mooney
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D052940:Merozoites / Q000187:drug effects; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D015800:Protozoan Proteins / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D010455:Peptides; D015800:Protozoan Proteins