Synthetic Model of Nanostructured, Functionalized Peptide Matrix

The concept of intramolecular catalysis, in which a reaction is accelerated by the participation of a neighbouring group in a reactant, is well established in organic chemistry. We look to intramolecular catalysis in enzymes by substrate participation. The catalytic efficacy of enzymes stems, in part, from their well-defined folded structure. Within the active site, catalytic residues are precisely oriented in space to accommodate well orchestrated, and often highly stabilized, transition states. Our approach involves the synthesis of minimal peptides containing the key features of enzymatic active sites and the insertion of this sequence in a peptidic matrix in order to obtain a substantially simplified chiral environment. In general, the design of peptide-based catalysts have largely focused on sequences that are predisposed to specific secondary structures. The ?-turn motif has proved particularly fruitful in this regard. Based on our studies of synthetic homologues of protein-derived exorphins [1], we sought to take advantage of predictable ?-turn geometry in our catalyst design. In many cases, the tendency of certain ?-turn-containing peptides to adopt double stranded structures provides further conformational support through additional interstrand hydrogen bonds. This approach allows for the possibility of positioning catalytically active amino acid side chains in close proximity to the substrate as well as to other functional groups that further stabilize the catalytic complex. Several factors are for key importance in design of a peptidic matrix that contains the catalyst and serves as template for the growing polypeptide chain, including (i) conformational and dynamical properties of template, (ii) the nature and role of ?-turn, (iii) nature of the stabilising weak interactions. Here we report about synthesis and conformational characteristics of model systems containing two bioactive sequences covalently bonded to side chains functional groups of the template peptide (Image_01).