2006 lecture series

61th IBB Seminar
- Protein Epitope Mimetics in Drug and Vaccine Research -

Abstract: The design and synthesis of novel ligands for protein and nucleic acid receptors are important goals in post-genomic proteome analysis and in drug and vaccine research. Described here is an approach to the design of protein and nucleic acid ligands based on synthetic peptidomimetics that adopt constained beta-hairpin conformations. A conformationally constrained beta-hairpin motif represents a robust scaffold upon which groups important for receptor recognition can be displayed. Beta-Hairpin epitope mimetics can be produced in a parallel fashion, by assembling recognition loops onto beta-hairpin-inducing templates. This approach has afforded good structural mimics of canonical antibody CDR loops, and has been applied to develop potent biologically active mimetics of naturally occurring beta-hairpin-peptides. This includes cationic antimicrobial peptides, serine protease inhibitors, HIV entry inhibitors derived from the CXCR4 antagonist polyphemusin, and RNA ligands based on the Tat protein of HIV that binds to the TAR RNA. Another recent demonstration of the robustness of the beta-hairpin scaffold is the design and optimization of a family of beta-hairpin mimetic inhibitors of the alpha−helical p53 epitope recognized by the protein HDM2. Recent structural investigations, including an X-ray structure of one beta-hairpin mimetic bound to HDM2 have provided important insights into the mechanisms of ligand recognition. Finally, not only receptor affinity but also drug-like properties can be optimized in these beta-hairpin mimetics, as demonstrated by the discovery of a potent and highly selective CXCR4 antagonist that shows high serum stability and good bioavailability.

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