| The α-helix is one of the most common structures found on the surface of proteins. Molecules that recognize, stabilize or mimic this secondary structure have the potential to modulate protein-protein interactions and may have pharmaceutical applications.; First, a series of protected, 1,3-substituted guanidine containing compounds were synthesized in order to establish methodology for mild guanylation. A number of amines with different electronic and steric properties were used to determine the versatility of our method. Yields ranged from near quantitative for electron rich, unhindered amines, to complete lack of conversion for bulky amines.; Second, a receptor for an α-helical peptide was designed. The idea was to use the knowledge gleaned from our group's work on tetrakis bicyclic guanidinium receptors that have been shown to bind to tetra-Asp-containing, helical peptides. The new molecule contained a naphthalene flanked by two bicyclic guanidinium groups. A number of peptide sequences were synthesized with different orientations between the recognition elements. Binding studies were performed, however, no binding was observed.; As an alternative, a series of peptides containing four Asp residues flanked by four aromatic residues was designed, based on a classic molecular-recognition system, to bind to a tetetrakis-bisguanidinium receptor. These peptides bound with a stronger affinity and in a more aqueous media than the peptide with no aromatic amino acids as demonstrated by CD and fluorescence spectroscopies. These data suggested that we could design a de novo protein surface to recognize a small molecule receptor.; Extending our work with the α-helix and with protein surface recognition, we set out to establish a general method for the synthesis and mimicry of one face of a peptide helix. Our design uses a terphenyl scaffold to project functionality similar to that of two turns of a helix and greatly reduces the flexibility and molecular weight. As a proof of concept, we applied this system to the α-helix binding protein calmodulin (CaM). A number of terphenyl mimics of smooth-muscle myosin light chain kinase (smMLCK) were shown to bind to CaM and inhibit the CaM activation of phosphodiesterase (a CaM dependent enzyme) with high activity. |
