Novel Bioactive Conformation Constructed by Structurally Constrained CH/π Interaction between Amino Acids Side Chains

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The CH/π interaction between alkyl group (CH donor) and benzene ring (π donor) is a kind of hydrogen bondings, and is important to construct a particular three-dimensional structure of proteins. The goal of the present study is to establish a novel method to constrain the bioactive conformation of peptides by constructing such a CH/π interaction between amino acid side chains in order to create a novel biologically active peptide. The CH/π interaction should become a structural essential with the hydrophobic core. Dipeptide Leu-Phe with the D-L configurational sequence constructs a typical CH/π interaction between Leu-isobutyl group and Phe-phenyl group. This dipeptide has a N-terminal free amino group and a C-terminal free carboxyl group. If we are able to load a structural element to induce a specific interaction with the target peptide or protein molecule(s), the derivative would be a new type of agonist, inhibitors of the target. We have succeeded in the design and synthesis of spe … More cific inhibitors of a series of serine proteases by conjugating a group that binds to the substraterecognition site of each enzyme. When the benzyl group was combined to the C-terminal carboxyl group, the resulting D-Leu-Phe benzyl amide was found to be a strong inhibitor of chymotrypsin. When the para-hydrogen of this benzyl group was replaced by the guanidine group, the derivative showed no inhibition for chymotrypsin. Instead, it strongly inhibited trypsin, another type serine protease. Thus, several series of compounds were newly synthesized as inhibitors of trypsin and chymotrypsin. The results clearly indicate that the dipeptide unit D-Leu-Phe can be a structural core to load an element to function as a novel bioactive peptide. The procedure employed in this study will definitely open a new field in the structure-activity studies of peptide sciences.In order to strengthen the CH/π interaction, it is important to search the structures more suitable as a CH donor or as a π donor. As CH donors we have designed a series of amino acids, the side chains of which contain the methylamine group, (-N)CH3n (n=1, 2, and 3). In addition, we achieved the synthesis of the phenylalanine derivatives, as strong π donors the phenylhydrogens of which were substituted with halogens. For instance, meta-bromo-para-fluorophenylalanine increased the activity of thrombin receptor-tethered ligand peptide SFLLRNF about six times when it was incorporated into this SFLLRNP at position 2. Apparently, this is a new way to enhance the activity by reinforcing the structurally restricted CH/π interaction. Thus, the major goal of this research project was achieved with enormous scientific successes. Less