title: Novel African trypanocidal agents: membrane rigidifying peptides.
abstract: The bloodstream developmental forms of pathogenic African trypanosomes are uniquely susceptible to killing by small hydrophobic peptides. Trypanocidal activity is conferred by peptide hydrophobicity and charge distribution and results from increased rigidity of the plasma membrane. Structural analysis of lipid-associated peptide suggests a mechanism of phospholipid clamping in which an internal hydrophobic bulge anchors the peptide in the membrane and positively charged moieties at the termini coordinate phosphates of the polar lipid headgroups. This mechanism reveals a necessary phenotype in bloodstream form African trypanosomes, high membrane fluidity, and we suggest that targeting the plasma membrane lipid bilayer as a whole may be a novel strategy for the development of new pharmaceutical agents. Additionally, the peptides we have described may be valuable tools for probing the biosynthetic machinery responsible for the unique composition and characteristics of African trypanosome plasma membranes.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Harrington
authors.forename: Chris
authors.initials: C
authors.lastname: Scelsi
authors.forename: Andreas
authors.initials: A
authors.lastname: Hartel
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Jones
authors.forename: Markus
authors.initials: M
authors.lastname: Engstler
authors.forename: Paul
authors.initials: P
authors.lastname: Capewell
authors.forename: Annette
authors.initials: A
authors.lastname: MacLeod
authors.forename: Stephen
authors.initials: S
authors.lastname: Hajduk
mesh_terms: D000349:Africa; D000595:Amino Acid Sequence; D055592:Biophysical Phenomena / Q000187:drug effects*; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D008051:Lipid Bilayers / Q000737:chemistry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects*; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000378:metabolism
chemical_list: D008051:Lipid Bilayers; D010455:Peptides; D014344:Trypanocidal Agents; D014643:Variant Surface Glycoproteins, Trypanosoma