IRST INSIGHTS IN THE STRUCTURE-FUNCTION RELATIONSHIP OF A NATURAL CYCLIC LIPODEPSIPEPTIDE
BY SYNTHETIC MODIFICATION
M. De Vleeschouwer 1,2 , D. Sinnaeve 1 , N. Matthijs 3 , T. Coenye 3 , J.C. Martins 1
,
A. Madder 2
1 NMR and Structure Analysis Unit, Department of Organic Chemistry, Ghent University
2 Organic and Biomimetic Chemistry Research Group, Department of Organic Chemistry, Ghent
University
3 Laboratory of Pharmaceutical Microbiology, Department of Pharmaceutical Analysis, Ghent University
Pseudodesmin A (1) is a secondary metabolite produced by Pseudomonas bacteria, belonging to the viscosin group of cyclic lipodepsipeptides. It displays moderate antibiotic activity, including against
MRSA and vancomycin-resistant Enterococcus. Extensive NMR studies revealed that individual molecules self-assemble into well-defined supramolecular structures in non-polar solvents.
[1,2] loop
D-Ser8
L-Leu7
D-Ser6
L-Ile9

L
-helix
HDA L-Leu1
Figure 1. Covalent structure, conformation and model for the supramolecular structure of pseudodesmin A
Our goal is to investigate in detail 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 for pseudodesmin A was developed.
[3] 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. 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.
[1] D. Sinnaeve, P.M.S Hendrickx, J. Van hemel, E. Peys, B. Kieffer and J.C. Martins, Chem. Eur. J., 15, 12653 (2009)
[2] D. Sinnaeve, M.A. Delsuc, J.C. Martins and B. Kieffer, Chem. Sci., 3, 1284 (2012)
[3] M. De Vleeschouwer D. Sinnaeve, J. Van den Begin, T. Coenye, J.C. Martins and A. Madder, Chem. Eur. J., (2014), in press,
DOI: 10.1002/chem.201402066