Analogs of pancreatic polypeptide and peptide YY with a locked PP-fold structure are biologically active |
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| Institution: | 1. Divisions of Thoracic Surgery;2. Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy;3. Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda;4. Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, USA;5. Division of Medical Oncology, Ospedali Galliera, Genoa;6. Division of Radiology, European Institute of Oncology, Milan;7. University of Milan, Milan;8. Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy;1. Physical Chemistry Department, Faculty of Pharmacy, University of Barcelona, CSIC-Associated Unit: Peptides and Proteins: Physicochemical Studies, IN2UB Av. Joan XXIII s/n, 08028 Barcelona, Spain;2. Unit of Synthesis and Biomedical Application of Peptides, Department of Biomedical Chemistry, IQAC-CSIC, Jordi Girona 18, 08034, Barcelona, Spain;3. Dept. de Bioquímica y Biología Molecular I, Facultad de Biología, Universidad Complutense, 28040 Madrid, Spain |
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| Abstract: | Pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY), members of the PP-fold family share a high degree of sequence homology. Nuclear magnetic resonance (NMR) and X-ray crystallography studies have shown these peptides can adopt a tightly organized tertiary structure called the PP-fold, which has long been assumed to be the active structure of this family of peptides. To date, however, no studies have been completed with PYY and PP which confirm if the PP-fold structure is important for their physiological actions. The aim of the study was to test if PYY and PP locked into the PP-fold maintained biological activity. Therefore, we designed and produced analogs of PP and PYY in a cyclic conformation with two cysteine amino acid substitutions at the N-terminus and at position 27. These were oxidized to form a cysteine disulfide bond locking the peptides into the PP-fold structure. Studies demonstrate that the cyclic analogs have both similar in vivo activity to their parent molecules, and affinity for the Y2 and Y4 receptors. Results suggest that the proposed PP and PYY-fold is likely to be their biologically active conformation. |
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