Beta-strand peptidomimetics as potent PDZ ligands

ORGN 945

Ming C. Hammond, ming.hammond@yale.edu1, Baruch Z. Harris2, Wendell A. Lim2, and Paul A. Bartlett3. (1) Department of Molecular, Cellular, and Developmental Biology, Yale University, PO Box 208103, New Haven, CT 06520, (2) Department of Cell and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, (3) Center for New Directions in Organic Synthesis, University of California, Berkeley, CA 94720
Research into general strategies for inhibiting protein-protein interactions has been stimulated by recognition of the key role they play in virtually every feature of living systems. Multi-protein complex assembly and localization by PDZ domain-containing proteins exemplify a process critical to cell physiology and function which is mediated by beta-strand association. Here we present the design and synthesis of peptidomimetics incorporating conformationally restricted amino acid surrogates that reproduce the hydrogen-bonding pattern and side chain functionality of a beta-strand. Comparison between these peptidomimetics and conventional peptides as ligands for the PDZ domain of α1-syntrophin reveal the importance of conformational restriction as well as specific side chain interactions in the enhanced binding affinity of the peptidomimetic.

 

Proteins, Peptides, Amino Acids, and Enzyme Inhibitors
1:00 PM-5:00 PM, Thursday, 14 September 2006 Moscone Center -- Room 131, Oral

Division of Organic Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006