@article{HarringtonScelsiHarteletal.2012,
  author    = {Harrington, John M. and Scelsi, Chris and Hartel, Andreas and Jones, Nicola G. and Engstler, Markus and Capewell, Paul and MacLeod, Annette and Hajduk, Stephen},
  title     = {Novel African Trypanocidal Agents: Membrane Rigidifying Peptides},
  series = {PLoS One},
  volume    = {7},
  journal   = {PLoS One},
  number    = {9},
  doi       = {10.1371/journal.pone.0044384},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135179},
  pages     = {e44384},
  year      = {2012},
  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.},
  language  = {en}
}
@article{KochCappelNockeretal.2013,
  author    = {Koch, Oliver and Cappel, Daniel and Nocker, Monika and J{\"a}ger, Timo and Floh{\´e}, Leopold and Sotriffer, Christoph A. and Selzer, Paul M.},
  title     = {Molecular Dynamics Reveal Binding Mode of Glutathionylspermidine by Trypanothione Synthetase},
  series = {PLoS ONE},
  volume    = {8},
  journal   = {PLoS ONE},
  number    = {2},
  doi       = {10.1371/journal.pone.0056788},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131070},
  pages     = {e56788},
  year      = {2013},
  abstract  = {The trypanothione synthetase (TryS) catalyses the two-step biosynthesis of trypanothione from spermidine and glutathione and is an attractive new drug target for the development of trypanocidal and antileishmanial drugs, especially since the structural information of TryS from Leishmania major has become available. Unfortunately, the TryS structure was solved without any of the substrates and lacks loop regions that are mechanistically important. This contribution describes docking and molecular dynamics simulations that led to further insights into trypanothione biosynthesis and, in particular, explains the binding modes of substrates for the second catalytic step. The structural model essentially confirm previously proposed binding sites for glutathione, ATP and two \(Mg^{2+}\) ions, which appear identical for both catalytic steps. The analysis of an unsolved loop region near the proposed spermidine binding site revealed a new pocket that was demonstrated to bind glutathionylspermidine in an inverted orientation. For the second step of trypanothione synthesis glutathionylspermidine is bound in a way that preferentially allows \(N^1\)-glutathionylation of \(N^8\)-glutathionylspermidine, classifying \(N^8\)-glutathionylspermidine as the favoured substrate. By inhibitor docking, the binding site for \(N^8\)-glutathionylspermidine was characterised as druggable.},
  language  = {en}
}