Pancreatic Polypeptide (human)

High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C-Terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination, and Radiolabeling.[Pubmed:27223253]

J Med Chem. 2016 Jul 14;59(13):6045-58.

The diastereomeric mixture of d/l-2,7-diaminooctanedioyl-bis(YRLRY-NH2) (BVD-74D, 2) was described in the literature as a high affinity Y4 receptor agonist. Here we report on the synthesis and pharmacological characterization of the pure diastereomers (2R,7R)- and (2S,7S)-2 and a series of homo- and heterodimeric analogues in which octanedioic acid was used as an achiral linker. To investigate the role of the Arg residues, one or two arginines were replaced by Ala. Moreover, N(omega)-(6-aminohexylaminocarbonyl)Arg was introduced as an arginine replacement (17). (2R,7R)-2 was superior to (2S,7S)-2 in binding and functional cellular assays and equipotent with 17. [(3)H]Propionylation of one amino group in the linker of (2R,7R)-2 or at the primary amino group in 17 resulted in high affinity Y4R radioligands ([(3)H]-(2R,7R)-10, [(3)H]18) with subnanomolar Kd values.

Pancreatic beta-Cell Membrane Fluidity and Toxicity Induced by Human Islet Amyloid Polypeptide Species.[Pubmed:26880502]

Sci Rep. 2016 Feb 16;6:21274.

Aggregation of human islet amyloid polypeptide (hIAPP) into fibrils and plaques is associated with pancreatic beta-cell loss in type 2 diabetes (T2D). However, due to the rapidness of hIAPP conversion in aqueous phase, exactly which hIAPP species is responsible for the observed toxicity and through what mechanisms remains ambiguous. In light of the importance of understanding hIAPP toxicity for T2D here we show a biophysical scheme based on the use of a lipophilic Laurdan dye for examining MIN6 cell membranes upon exposure to fresh and oligomeric hIAPP as well as mature amyloid. It has been found that all three hIAPP species, especially fresh hIAPP, enhanced membrane fluidity and caused losses in cell viability. The cell generation of reactive oxygen species (ROS), however, was the most pronounced with mature amyloid hIAPP. The correlation between changes in membrane fluidity and cell viability and their lack of correlation with ROS production suggest hIAPP toxicity is elicited through both physical and biochemical means. This study offers a new insight into beta-cell toxicity induced by controlled hIAPP species, as well as new biophysical methodologies that may prove beneficial for the studies of T2D as well as neurological disorders.

High molecular weight PEGylation of human pancreatic polypeptide at position 22 improves stability and reduces food intake in mice.[Pubmed:27545829]

Br J Pharmacol. 2016 Nov;173(22):3208-3221.

BACKGROUND AND PURPOSE: Human pancreatic polypeptide (hPP) is known to suppress appetite and food intake, thereby representing a potential therapeutic approach against obesity and associated metabolic disorders. The aim of this study was to improve hPP stability by covalent PEGylation with diverse molecular weight polyethylene glycols (PEGs) at two positions using promising lead structures while maintaining target activity. EXPERIMENTAL APPROACH: Modified peptides were synthesized by combined solid-phase and solution-phase peptide synthesis. Their potency was investigated in constitutively expressing human epithelial cells and isolated human colonic mucosa as well as receptor-transfected artificial cell lines. Human blood plasma and porcine liver homogenates were used to examine the in vitro stability of the analogues. The most promising variants were injected s.c. in C57BL/6JRj mice to monitor fasting-induced food intake and bioavailability. KEY RESULTS: In human epithelia and colonic mucosal preparations, activity of the modified hPP peptides depended on the core sequence and latency of the peptides was related to PEG size. Peptides modified with a 22 kDa PEG (PEG22) remained intact in blood plasma and on incubation with liver homogenates for more than 96 h. Finally, hPP2-36 , [K(22) (PEG22)]hPP2-36 and [K(22) (PEG22),Q(34) ]hPP significantly reduced cumulative food intake in mice over 16 h after s.c. administration. CONCLUSIONS AND IMPLICATIONS: Modification with PEG22 at position 22 stabilizes hPP significantly while extending its biological activities and could be used in drug development prospectively.

Protein disulfide isomerase ameliorates beta-cell dysfunction in pancreatic islets overexpressing human islet amyloid polypeptide.[Pubmed:26607804]

Mol Cell Endocrinol. 2016 Jan 15;420:57-65.

Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits in islets of type 2 diabetic patients. hIAPP misfolding and aggregation is one of the factors that may lead to beta-cell dysfunction and death. Endogenous chaperones are described to be important for the folding and functioning of proteins. Here, we examine the effect of the endoplasmic reticulum chaperone protein disulfide isomerase (PDI) on beta-cell dysfunction. Among other chaperones, PDI was found to interact with hIAPP in human islet lysates. Furthermore, intrinsically recovered PDI levels were able to restore the effect of high glucose- and palmitate-induced beta-cell dysfunction by increasing 3.9-fold the glucose-stimulated insulin secretion levels and restoring insulin content up to basal control values. Additionally, PDI transduction decreased induced apoptosis by glucolipotoxic conditions. This approach could reveal a new therapeutic target and aid in the development of strategies to improve beta-cell dysfunction in type 2 diabetic patients.

Multiple receptors for the pancreatic polypeptide (PP-fold) family: physiological implications.[Pubmed:9572148]

Proc Soc Exp Biol Med. 1998 May;218(1):7-22.

The pancreatic polypeptide (PP-fold) family of peptides consists of the endocrine peptides, pancreatic polypeptide (PP) and peptide YY (PYY), and the neuroneally derived peptide, neuropeptide Y (NPY). All three peptides are found in the circulation, with PP found primarily in the pancreas and PYY found principally in the gut. NPY is released into the circulation from neuroneal stores in response to stress. These peptides have broad peripheral actions on a number of organs. Not surprisingly, PYY and PP are believed to play an important role in the function of the gastrointestinal tract while NPY is a potent vasconstrictor and may have effects on the gut through the enteric nervous system. In the brain, NPY has been implicated in anxiety and depression, feeding and obesity, memory retention, neuroneal excitability, endocrine function, and metabolism. Recent advances in the molecular biology of the receptors for these peptides have resulted in the identification of at least six receptor subtypes with varying peptide pharmacology. Compared to other G-protein coupled receptor families, the PP-fold peptide receptors exhibit a relatively low level of sequence identity. Further advances in the development of selective agonists and antagonists for individual receptor subtypes will be needed to understand further their role in physiological function.

Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY.[Pubmed:7592911]

J Biol Chem. 1995 Nov 10;270(45):26762-5.

The pancreatic polypeptide family includes pancreatic polypeptide (PP), neuropeptide Y (NPY), and peptide YY (PYY). Members of the PP family regulate numerous physiological processes, including appetite, gastrointestinal transit, anxiety, and blood pressure. Of the multiple Y-type receptors proposed for PP family members, only the Y1 subtype has been cloned previously. We now report the cloning of an additional Y-type receptor, designated Y4, by homology screening of a human placental genomic library with transmembrane (TM) probes derived from the rat Y1 gene. The Y4 genomic clone encodes a predicted protein of 375 amino acids that is most homologous to Y1 receptors from human, rat, and mouse (42% overall; 55% in TM). 125I-PYY binding to transiently expressed Y4 receptors was saturable (pKd = 9.89) and displaceable by human PP family derivatives: PP (pKi = 10.25) approximately PP2-36 (pKi = 10.06) > PYY (pKi = 9.06) approximately [Leu31,Pro34]NPY (pKi = 8.95) > NPY (pKi = 8.68) > PP13-36 (pKi = 7.13) > PP31-36 (pKi = 6.46) > PP31-36 free acid (pKi < 5). Human PP decreased [cAMP] and increased intracellular [Ca2+] in Y4-transfected LMTK- cells. Y4 mRNA was detected by reverse transcriptase-polymerase chain reaction in human brain, coronary artery, and ileum, suggesting potential roles for Y4 receptors in central nervous system, cardiovascular, and gastrointestinal function.

Pancreatic Polypeptide, human is a C-terminally amidated 36 amino acid peptide, which acts as a neuropeptide Y (NPY) Y4/Y5 receptor agonist.

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