Poster Presentation 12th Australian Peptide Conference 2017

Understanding structure, self-assembly and biological activity of natural cyclic lipodepsipeptides by synthetic modification (#172)

Annemieke Madder 1 , Matthias De Vleeschouwer 1 2 , Yentl Verleysen 1 2 , Nele Matthijs 3 , Davy Sinnaeve 2 , Niels Geudens 2 , Tom Coenye 3 , Jose C Martins 2
  1. Department of Organic and Macromolecular Chemistry / Organic and Biomimetic Chemistry Research Group, Ghent University, Ghent, Belgium
  2. Department of Organic and Macromolecular Chemistry / NMR and Structure Analysis Unit, Ghent University, Ghent, Belgium
  3. Department of Pharmaceutical Analysis / Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium

Cyclic lipodepsipeptides (CLPs) produced by Pseudomonads constitute a large group of secondary metabolites characterized by an oligopeptide chain, C-terminally involved in the formation of a depsipeptide bond through macrolactonization and N-terminally linked to a fatty acid moiety. Despite their clinical and agriculture related potential, the molecular mechanism of action of CLPs remains yet to be determined.

In order to allow full exploitation of the promising properties of these compounds, considerable efforts are currently devoted to isolate, identify and characterize the activity profile of such CLPs. Establishing structure-function relationships and understanding their interactions with biological membranes at the molecular level are key requirements for the further development of these compounds.

Extensive NMR studies revealed that individual molecules self-assemble into well-defined supramolecular structures in non-polar solvents.[1,2] We became interested in exploring the molecular structure of the self-assembly and its role in biological activity, which involves membrane interaction. For this, a rapid, efficient solid-phase synthesis strategy was developed, which has vastly expanded the chemical space previously limited to natural variations.[3,4,5] The newly developed route allows the straightforward production of analogues for structure-activity relationship studies, including an Ala-scan and modifications to the fatty acid moiety. Over 40 variations have been designed, synthesized and evaluated for biological activity. Using NMR diffusion measurements, the modulation of the self-assembly could be monitored, revealing fundamental intermolecular contacts. Additionally, the enantiomer of pseudodesmin A was produced, revealing identical biological activity, for the first time demonstrating that no chiral interactions mediate these compounds’ mode of action.

The impact of amino acid composition, stereochemistry and lipid tail length on biological activity allow us to identify several key-modulators of biological activity, which are interpreted in terms of the three dimensional structures obtained using NMR and/or X-ray diffraction.

  1. 1. D. Sinnaeve, P.M.S. Hendrickx, J. Van Hemel et al. Chem. Eur. J. 2009, 15, 12653-12662. 2. D. Sinnaeve, M.A. Delsuc, J.C. Martins and B. Kieffer. Chem. Sci. 2012, 3, 1284-1292 3. M. De Vleeschouwer, D. Sinnaeve, J. Van den Begin et al. Chem. Eur. J., 2014, 20, 7766-7775. 4. M. De Vleeschouwer, J. C. Martins, and A. Madder. J. Peptide Science, 2016, 22, 149-155. 5. M. De Vleeschouwer, D. Sinnaeve, N. Matthijs, T. Coenye, A. Madder and J. C. Martins. Chemistry Select, 2017, 2, 640–644.