text: Discovery and structural characterization of a phospholamban-binding cyclic peptide and design of novel inhibitors of phospholamban.
  The interplay between cardiac sarcoplasmic Ca(2+)ATPase and phospholamban is a key regulating factor of contraction and relaxation in the cardiac muscle. In heart failure, aberrations in the inhibition of sarcoplasmic Ca(2+)ATPase by phospholamban are associated with anomalies in cardiac functions. In experimental heart failure models, modulation of the interaction between these two proteins has been shown to be a potential therapeutic approach. The aim of our research was to find molecules able to interfere with the inhibitory activity of phospholamban on sarcoplasmic Ca(2+)ATPase. For this purpose, a portion of phospholamban was synthesized and used as target for a phage-display peptide library screening. The cyclic peptide C-Y-W-E-L-E-W-L-P-C-A was found to bind to phospholamban (1-36) with high specificity. Its functional activity was tested in Ca(2+)uptake assays utilizing preparations from cardiac sarcoplasmic reticulum. By synthesizing and testing a series of alanine point-mutated cyclic peptides, we identified which amino acid was important for the inhibition of the phospholamban function. The structures of active and inactive alanine-mutated cyclic peptides, and of phospholamban (1-36), were determined by NMR. This structure-activity analysis allowed building a model of phospholamban -cyclic peptide complex. Thereafter, a simple pharmacophore was defined and used for the design of small molecules. Finally, examples of such molecules were synthesized and characterized as phospholamban inhibitors.
entities.id: T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T2 T3 T4 T5 T6 T7 T8 T9
entities.type: GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-Y GENE-N GENE-Y CHEMICAL GENE-Y GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y
entities.text: cyclic peptides phospholamban (1-36) phospholamban phospholamban Ca(2+)ATPase phospholamban Ca(2+)ATPase phospholamban Ca(2+)ATPase phospholamban amino acid phospholamban C-Y-W-E-L-E-W-L-P-C-A phospholamban (1-36) phospholamban phospholamban alanine Ca(2+) Ca(2+) Ca(2+) Ca(2+) alanine cyclic peptides phospholamban