Novel African Trypanocidal Agents: Membrane Rigidifying Peptides

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.

[1]  O. Gabrielli,et al.  Alterations of platelet biochemical and functional properties in newly diagnosed type 1 diabetes: a role in cardiovascular risk? , 2011, Diabetes/metabolism research and reviews.

[2]  S. Hajduk,et al.  The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides* , 2010, The Journal of Biological Chemistry.

[3]  Guy Hendrickx,et al.  A changing environment and the epidemiology of tsetse-transmitted livestock trypanosomiasis. , 2010, Trends in parasitology.

[4]  L. Marcello,et al.  Antigenic variation in the African trypanosome: molecular mechanisms and phenotypic complexity , 2009, Cellular microbiology.

[5]  T. Hazlett,et al.  Flagellar membrane localization via association with lipid rafts , 2009, Journal of Cell Science.

[6]  B. Dahlbäck,et al.  Apolipoprotein M associates to lipoproteins through its retained signal peptide , 2008, FEBS letters.

[7]  K. Matthews,et al.  The cell biology of Trypanosoma brucei differentiation. , 2007, Current Opinion in Microbiology.

[8]  Stephan Herminghaus,et al.  Hydrodynamic Flow-Mediated Protein Sorting on the Cell Surface of Trypanosomes , 2007, Cell.

[9]  S. Moestrup,et al.  Hemoglobin Is a Co-Factor of Human Trypanosome Lytic Factor , 2007, PLoS pathogens.

[10]  Gajendra P.S. Raghava,et al.  PEPstr: a de novo method for tertiary structure prediction of small bioactive peptides. , 2007, Protein and peptide letters.

[11]  Nathan A. Baker,et al.  PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations , 2004, Nucleic Acids Res..

[12]  Michael P Barrett,et al.  The trypanosomiases , 2003, The Lancet.

[13]  J. Crowe,et al.  Temperature dependence of fluid phase endocytosis coincides with membrane properties of pig platelets. , 2003, Biochimica et biophysica acta.

[14]  H. Schwarz,et al.  Accumulation of a GPI‐Anchored Protein at the Cell Surface Requires Sorting at Multiple Intracellular Levels , 2002, Traffic.

[15]  L. Voglino,et al.  Orientation of LamB signal peptides in bilayers: influence of lipid probes on peptide binding and interpretation of fluorescence quenching data. , 1999, Biochemistry.

[16]  Stephen Tomlinson,et al.  Characterization of a Novel Trypanosome Lytic Factor from Human Serum , 1999, Infection and Immunity.

[17]  J. Killian,et al.  PhoE signal peptide inserts into micelles as a dynamic helix-break-helix structure, which is modulated by the environment. A two-dimensional 1H NMR study. , 1995, Biochemistry.

[18]  J. D. Jones,et al.  Effect of charged residue substitutions on the membrane-interactive properties of signal sequences of the Escherichia coli LamB protein. , 1994, Biophysical journal.

[19]  S. Hajduk,et al.  Lysis of Trypanosoma brucei by a toxic subspecies of human high density lipoprotein. , 1989, The Journal of biological chemistry.

[20]  T. McIntosh,et al.  Determination of the depth of bromine atoms in bilayers formed from bromolipid probes. , 1987, Biochemistry.

[21]  E. London,et al.  Parallax method for direct measurement of membrane penetration depth utilizing fluorescence quenching by spin-labeled phospholipids. , 1987, Biochemistry.

[22]  L. Gierasch,et al.  Conformations of signal peptides induced by lipids suggest initial steps in protein export. , 1986, Science.

[23]  Thomas Efferth,et al.  Development of drug resistance in Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Treatment of human African trypanosomiasis with natural products (Review). , 2008, International journal of molecular medicine.

[24]  N. Greenfield.  Using circular dichroism spectra to estimate protein secondary structure , 2007, Nature Protocols.

[25]  S. Hajduk,et al.  African Trypanosomes: Intracellular Trafficking of Host Defense Molecules 1 , 2007, The Journal of eukaryotic microbiology.

[26]  Tom Misteli,et al.  Measurement of dynamic protein binding to chromatin in vivo, using photobleaching microscopy. , 2004, Methods in enzymology.

[27]  Monica F. Myers,et al.  Trypanosoma vivax – out of Africa , 2001 .