title: Beta strand peptidomimetics as potent PDZ domain ligands.
abstract: The search for general strategies for inhibiting protein-protein interactions has been stimulated by recognition of the key role they play in virtually every process of living systems. Multiprotein complex assembly and localization by PDZ domain-containing proteins exemplify processes critical to cell physiology and function that are mediated by beta strand association. Here we describe the development of substituted "@-tides," protease-resistant peptidomimetics incorporating conformationally restricted amino acid surrogates that reproduce the hydrogen-bonding pattern and side-chain functionality of a beta strand. The synthetic flexibility and generality of the substituted @-tide design was demonstrated by the synthesis of a panel of ligands for the alpha1-syntrophin PDZ domain. The rational design of a small molecule of unprecedented affinity for the PDZ domain suggests that these peptidomimetics may provide a general method for inhibiting protein-protein interactions involving extended peptide chains.
authors.affiliation: Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, USA.
authors.forename: Ming C
authors.initials: MC
authors.lastname: Hammond
authors.forename: Baruch Z
authors.initials: BZ
authors.lastname: Harris
authors.forename: Wendell A
authors.initials: WA
authors.lastname: Lim
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bartlett
mesh_terms: D032701:Biomimetics; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009124:Muscle Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: D002135:Calcium-Binding Proteins; D008024:Ligands; D008565:Membrane Proteins; D009124:Muscle Proteins; C091825:syntrophin alpha1