Introduction of conformational restraints in peptides is a very useful means to probe peptide-receptor interactions and to enhance potency and/or selectivity. While local conformational restraints can be imposed by incorporation of unsaturated or small ring amino acids, side chain-side chain cyclization to form cyclic analogues has proved to be one of the most useful approaches for the introduction of more general conformational constraints: e.g., a disulfide bond between Cys or Pen residues, or an amide bond between side chains of amino and carboxy triflunctional amino acids. The 13-member cyclic peptide, H-TRY-D-Orn-Phe-Asp-NH2 (cyc-Orn- Asp), is a potent u-selective opioid peptide. Molecular modeling of this peptide has revealed great flexibility in the ring structure, making it difficult to identify a single conformation which may be biologically relevant. In order to restrict further the conformational mobility in such peptides, we have designed and synthesized a novel trifunctional amino acid based on pyrrolidine (PDA). This amino acid, if used in place of Orn or Lys for side chain-side chain cyclization, is expected to reduce considerably the conformational flexibility in the macrocyclic ring of these peptides owing to the introduction of a cyclic structure. Moreover, the additional asymmetric center in the pyrrolidine ring may introduce differential stereochemical constraints to the binding of diastereoisomeric peptides, derived from the corresponding diastereoismeric PDA's. Thus, these peptides may act as probes for delineating the stereochemical topology of the receptor in the vicinity of the ring structure and may have useful biological properties and applications. Optically active amino acids are being used increasingly as synthons for the preparation of a variety of chiral compounds. PLA's can be expected to be excellent synthons for compounds such as pyrrolizidines with the stereochemistry already defined at two centers. Furthermore, these acids may possess antimicrobial or other antimetabolic activities. An efficient method for the synthesis of all four optically active stereoisomers of PDA has been developed. These amino acids will be used for the preparation of novel bicyclic opioid peptide analogues.
| Zhang, Ning; Appella, Daniel H (2010) Advantages of peptide nucleic acids as diagnostic platforms for detection of nucleic acids in resource-limited settings. J Infect Dis 201 Suppl 1:S42-5 |
