Discovery and Structural Characterization of a Phospholamban-Binding Cyclic Peptide and Design of Novel Inhibitors of Phospholamban
| Autor: | Piero Pollesello, Tiainen Eija, Jarmo Pystynen, Martti Ovaska, Carola Tilgmann, Jouko Levijoki, Marjo Yliperttula, Juha Kaivola, Arto Annila |
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| Rok vydání: | 2012 |
| Předmět: |
ATPase
Plasma protein binding 030204 cardiovascular system & hematology Biochemistry 03 medical and health sciences 0302 clinical medicine Drug Discovery medicine Peptide library Peptide sequence 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences biology Chemistry Endoplasmic reticulum Organic Chemistry Cardiac muscle musculoskeletal system Cyclic peptide 3. Good health Phospholamban medicine.anatomical_structure cardiovascular system biology.protein Molecular Medicine tissues circulatory and respiratory physiology |
| Zdroj: | Chemical Biology & Drug Design. 81:463-473 |
| ISSN: | 1747-0277 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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