Lead


Lay summary
This proposal aims to assemble amino acids to form dendritic and polycyclic topologies not found in naturally occurring peptides and proteins, and explore the biological properties of the resulting macromolecules. In nature amino acids assemble to form mostly linear or monocyclic structures. We have recently established efficient solid-phase peptide synthesis (SPPS) procedures to prepare peptides with branched (dendritic) and bicyclic topologies which are not accessible by natural biosynthetic pathways. Our preliminary results show that such peptides offer a promising and versatile platform for drug design. This line of research is original and has not been followed by other groups in peptide chemistry, where research is focused almost exclusively on linear or monocyclic peptide analogs of natural sequences . Synthesizing peptide topologies not found in nature such as peptide dendrimers and polycyclic peptides as proposed here provides an original and fundamentally new window of opportunity to design bioactive compounds.
Because peptide based molecules can be assembled with well established protocols from a diversity of amino acid building blocks, the versatility is very large. Furthermore, peptide based drugs have the advantage to pose relatively few toxicology and metabolisation problems because they are made of generally non-toxic amino acids. Beside its fundamental appeal in terms of expansion of the accessible chemical space into new areas, the project focuses on significant targets of current medicinal importance with significant preliminary activities in the area of antibiotics, gene therapy and cancer therapy, and might lead to innovative drugs.