Bicyclic Organo-Peptides as Models for Carbohydrate Binding Proteins

Abstract

Introduction Carbohydrate recognition is one of the most sophisticated recognition processes in biological systems. This process mediates many important aspects of cell-cell recognition, such as inflammation, cell differentiation, tumor cell colonization and metastasis. However, due to its complexity and weak binding affinities, carbohydrate recognition by natural systems is still poorly understood. On the other hand, studies on synthetic carbohydrate receptors could make significant contributions to a better understanding of this process and lead to the development of new therapeutics. Given the importance of the carbohydrate recognition, it is not surprising that design and synthesis of artificial receptors for these important biological substrates attracted a great deal of attention in biomimetic chemistry. Current efforts are mainly focused on design of the receptors for complexation of monosacharides or short oligosaccharides. This crude simplification has been based on the structural studies of the lectins, revealing that carbohydrate binding sites are typically shallow binding pockets where only binding of the terminal sugar moieties of complex polysaccharides can occur. Binding of an individual lectin to monosaccharide substrate is extremely weak; the dissociation constant (Kd) for these complexes are typically in the 0.1-10 mM. This is largely due to the solvent-exposed nature of the lectin binding sites, which make few direct contacts with monosaccharide substrate. Carbohydrate binding protein mimicking molecules using the peptide based systems represent particularly attractive approach for the development of artificial carbohydrate receptors. As a model system we chose a cyclic cationic decapeptide antibiotic polymyxin B, which is known to bind the lipid A moiety of LPS with the high affinity. Using standard Fmoc SPPS we prepared cyclic polymyxin analogue 1 bridged with a bipyridine group in order to introduce structural constraints pertaining to the stabilization of peptide’s binding conformation, and to incorporate additional hydrogen-bonding acceptor site. Therefore, this bicyclic organo-peptide receptor molecule possesses the necessary three-dimensional structure, limited flexibility and lipophilic binding pocket where binding can occur through a combination of hydrophobic interaction and possibly hydrogen bonds between receptor molecules and carbohydrate substrates.