Influence of CLP structure on antitumor potential

Cyclic lipodepsipeptides (CLPs) are generally produced by bacteria such as Pseudomonas and Bacillus as secondary metabolites. These amphiphilic compounds consist of an oligopeptide chain where a fatty acid moiety is linked to the N-terminus and cyclization occurs via ester-bond formation that involves the C-terminus. Although they have this quite characteristic molecular blueprint, substantial structural diversity can be observed between and within the existing groups. This is mainly as a consequence of variation in amino acid composition, including modified proteinogenic, non-proteinogenic and D-amino acids and the length and degree of saturation of the fatty acid moiety. Besides this high diversity in chemical features, CLPs also exhibit a broad range of diverse biological functions including antimicrobial, antifungal and antiviral activity. More recently, for some CLPs including viscosin, antitumoral activity has been described as well. Despite their potential in clinical and agricultural context, there is not much known about their mechanism of action – for Pseudomonas CLPs in particular – and the corresponding structure-activity relation of CLPs. Over the last few years, considerable knowledge and expertise have been acquired when it comes to isolation, characterisation and synthesis of CLPs, the latter with emphasis on members of the viscosin group. For instance, a rapid and efficient total chemical synthesis strategy has been developed[1][2] and an NMR and modelling methodology was established allowing a detailed understanding of CLP structure and conformation.[3][4] In this presentation, both expertise areas are combined in order to explore how differences in structure and composition of various CLPs may lead to variations in their antitumoral activity. References [1] M. De Vleeschouwer, D. Sinnaeve, J. Van den Begin, T. Coenye, J. C. Martins, A. Madder; Chem. - A Eur. J. 2014, 79, 1614–1621. [2] M. De Vleeschouwer, J. C. Martins, A. Madder; J. Pept. Sci. 2016, 22, 149–155. [3] N. Geudens, M. N. Nasir, J.-M. Crowet, J. M. Raaijmakers, K. Fehér, T. Coenye, J. C. Martins, L. Lins, D. Sinnaeve, M. Deleu; Biochim. Biophys. Acta - Biomembr. 2017, 1859, 331–339. [4] N. Geudens, M. De Vleeschouwer, K. Fehér, H. Rokni-Zadeh, M. G. K. Ghequire, A. Madder, R. De Mot, J. C. Martins, D. Sinnaeve; ChemBioChem 2014, 15, 2736–2746