The interdisciplinary project addresses research issues on the borderline between bioorganic chemistry, biochemistry, and medical sciences. It focuses on an important class of proteins, the integrins, employing organic synthesis of novel conformationally constrained amino acids, incorporation of such building blocks into peptides, as well as structural and functional characterization using methods of protein biochemistry, cell culture, NMR spectroscopy, and biophysical analysis. Integrins are heterodimeric cell surface glycoprotein receptors, involved in cellcell and cellmatrix adhesion.
The interaction of integrins with ligands is the molecular basis of physiological or pathological processes, such as platelet aggregation, tumour cell adhesion, wound healing, internalisation of pathogenic bacteria or leukocyte adhesion. Small molecules that interfere with this interaction can efficiently influence the cell-cell and cell-matrix interaction imparted by the integrin, being of potential interest in the therapy o f cancer and inflammatory diseases. The amino acid sequence RGD (arginine-glycine-aspartic acid), which is present on many of the natural ligands, is essential for the interaction between integrins and their corresponding ligands. Synthetic peptides containing the RGD sequence have emerged as promising starting point for the identification, synthesis and development of selective integrin ligands.
The incorporation of novel modified and conformationally constrained amino acids can greatly affect the secondary structure of the peptide, in such way that the synthetic ligands prefer to adopt a particular conformation. Consequently, these amino acids serve as useful tools in the de novo design of biologically active peptides, since the spatial orientation of the pharmacophoric groups, which are critical to the molecular recognition process and the ligand receptor interaction, can be defined by the incorporation of such residues in strategic positions.
Fields of science
Call for proposal
See other projects for this call