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Design, synthesis, Structural Characterization and biological evaluation of new peptidomimetics with a defined secondary structure

Final Activity Report Summary - FOLDAMERS (Design, synthesis, structural characterisation and biological evaluation of new peptidomimetics with a defined secondary structure)

Protein-Protein interactions are fundamental to biology and constitute an interesting target for medicinal chemistry projects investigating cell adhesion, signal transduction, proteolysis or protein folding diseases. The modulation of these interactions can be achieved through the design of ligands that possess the correct functionalisation and geometry. In this regards peptides and peptidomimetics play an important role, since they are known to display unprecedented structural and functional diversity, as well as adopting specific secondary structures relevant to those found in protein segments or substrate-bound peptides of interest. The research topic of the early stage research proposed by this network was to design and synthetise new peptidomimetics of biological interest characterise their secondary structure and finally screen their biological activities.

Several molecular scaffolds were prepared and were then inserted into peptidic sequences to evaluate their ability as inducers of peptide secondary structure. Some of these were found to induce a stable hairpin with inversion of the sense of propagation of the peptidic sequence. In other cases a helical folding was identified. These data were then used to optimise the molecular scaffolds as well as to design new structures possessing enhanced ability to adopt relevant secondary structures. A few peptidomimetics were then prepared containing the scaffolds and specific sequences of amino acids known to modulate specific protein-protein interactions and were screened for their biological activity.

In one particular case, cyclic peptidomimetics based on a novel bifunctional diketopiperazine scaffold and containing the Arg-Gly-Asp (RGD) sequence were prepared. These were tested in competitive binding assays with the alphaV-beta3 integrin, whose key role in angiogenesis, tumour progression and metastasis has been ascertained, and in cell adhesion studies on several cancer cellular lines, revealing a high potency of these derivatives.

A series of fluorinated pseudopeptides was identified as a new class of proteasome inhibitors. These new fluorinated pseudopeptides incorporate a trifluoromethyl-beta-hydrazino acid scaffold as a mimic of beta-strand, and have differential inhibitory capacities for CT-L, PA and T-L in micromolar range without effect on challenging proteolytic enzymes such as calpain and cathepsin B. These results were the starting point of a flagship project currently in our laboratory. New peptidomimetics mimicking beta-strands, were also designed and tested as inhibitors of HIV-1 protease (PR) dimerisation. These showed more hydrophilic and metabolically stable than the peptidic strands, still being active on either wild-type or mutated HIV proteases.

The training objective of the FOLDAMERS project was to create a very stimulating, international and interdisciplinary environment for the training of young researchers at the early stage of their scientific career. All the fellows financed for a 3 years period were part of a collaborative project between 2 partners and spent 2 years at one site and a third year at another site. As a result of the co-tutored project financed by this project, all the researchers were awarded joint titles by the Institutions involved in the co-tutored project and for which co-tutoring agreements were established.

In addition several ESR's coming from the host Institutions involved in the project as well as other Institutions spent a period of research in the three partner Universities thus strengthening the collaboration already existing among the three partners and also with other academic groups.