Bay 55-9837

The specific VPAC2 agonist Bay 55-9837 increases neuronal damage and hemorrhagic transformation after stroke in type 2 diabetic rats.[Pubmed:22981158]

Neuropeptides. 2013 Apr;47(2):133-7.

VPAC2 receptor is a potential target for the treatment of type 2 diabetes and may also convey neuroprotective effects. The aim of this study was to determine the potential efficacy of the VPAC2 receptor agonist Bay 55-9837 against stroke in type-2 diabetic Goto-Kakizaki (GK) rats. GK rats were treated intravenously once daily for 7 days with 0.25 or 0.025 nmol/kg Bay 55-9837 or vehicle before inducing stroke by transient middle cerebral artery occlusion. Treatments were then continued for 7 further days. The glycemic effects of Bay 55-9837 were assessed by measuring fasting blood glucose and oral glucose tolerance. The severity of stroke was measured by assessing ischemic volume. The results show that Bay 55-9837 is not effective in lowering fasting glycemia and does not facilitate glucose disposal. The highest dose of Bay 55-9837 (0.25 nmol/kg) led to increased mortality and brain hemorrhage when compared to control. The lower dose of Bay 55-9837 (0.025 nmol/kg) did not increase mortality rate but caused a threefold increase of the ischemic lesion size with signs of brain hemorrhages as compared to control. In conclusion, Bay 55-9837 did not show antidiabetic or antistroke efficacy in the type 2 diabetic GK rat. Contrarily, Bay 55-9837 treatment led to increased mortality and worsening of the severity of stroke.

Chitosan-decorated selenium nanoparticles as protein carriers to improve the in vivo half-life of the peptide therapeutic BAY 55-9837 for type 2 diabetes mellitus.[Pubmed:25378923]

Int J Nanomedicine. 2014 Oct 17;9:4819-28.

PURPOSE: As a potential protein therapeutic for type 2 diabetes mellitus (T2DM), Bay 55-9837 is limited by poor stability and a very short half-life in vivo. The purpose of this study was to construct a novel nanostructured biomaterial by conjugating Bay 55-9837 to chitosan-decorated selenium nanoparticles (CS-SeNPs) to prolong the in vivo half-life of Bay 55-9837 by reducing its renal clearance rate. MATERIALS AND METHODS: Bay 55-9837-loaded CS-SeNPs (BAY-CS-SeNPs) were prepared, and their surface morphology, particle size, zeta potential, and structure were characterized. The stability, protein-loading rate, and in vitro release of Bay 55-9837 from CS-SeNPs were also quantified. Additionally, a sensitive high-performance liquid chromatography (HPLC) assay was developed for the quantification of Bay 55-9837 in mouse plasma. Thereafter, mice were injected via the tail vein with either Bay 55-9837 or BAY-CS-SeNPs, and the plasma concentration of Bay 55-9837 was determined via our validated HPLC method at different time intervals postinjection. Relevant in vivo pharmacokinetic parameters (half-life, area under the curve from time 0 to last sampling point, observed clearance) were then calculated and analyzed. RESULTS: BAY-CS-SeNPs were successfully synthesized, with diameters of approximately 200 nm. BAY-CS-SeNPs displayed good stability with a high protein-loading rate, and the release process of Bay 55-9837 from the CS-SeNPs lasted for over 70 hours, with the cumulative release reaching 78.9%. Moreover, the conjugation of CS-SeNPs to Bay 55-9837 significantly reduced its renal clearance to a rate of 1.56 mL/h and extended its half-life to 20.81 hours. CONCLUSION: In summary, our work provides a simple method for reducing the renal clearance rate and extending the half-life of Bay 55-9837 in vivo by utilizing CS-SeNPs as nanocarriers.

VPAC2 receptor agonist BAY 55-9837 increases SMN protein levels and moderates disease phenotype in severe spinal muscular atrophy mouse models.[Pubmed:24405637]

Orphanet J Rare Dis. 2014 Jan 9;9:4.

BACKGROUND: Spinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. One of the treatment strategies for SMA is to induce the expression of the protein from the homologous SMN2 gene, a rescuing paralog for SMA. METHODS AND RESULTS: Here we demonstrate the promise of pharmacological modulation of SMN2 gene by Bay 55-9837, an agonist of the vasoactive intestinal peptide receptor 2 (VPAC2), a member of G protein coupled receptor family. Treatment with Bay 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. Importantly, Bay 55-9837 also ameliorated disease phenotype in severe SMA mouse models. CONCLUSION: Our findings suggest the VPAC2 pathway is a potential SMA therapeutic target.

Macrophage Resistance to HIV-1 Infection Is Enhanced by the Neuropeptides VIP and PACAP.[Pubmed:23818986]

PLoS One. 2013 Jun 20;8(6):e67701.

It is well established that host factors can modulate HIV-1 replication in macrophages, critical cells in the pathogenesis of HIV-1 infection due to their ability to continuously produce virus. The neuropeptides VIP and PACAP induce well-characterized effects on macrophages through binding to the G protein-coupled receptors VPAC1, VPAC2 and PAC1, but their influence on HIV-1 production by these cells has not been established. Here, we describe that VIP and PACAP reduce macrophage production of HIV-1, acting in a synergistic or additive manner to decrease viral growth. Using receptor antagonists, we detected that the HIV-1 inhibition promoted by VIP is dependent on its ligation to VPAC1/2, whereas PACAP decreases HIV-1 growth via activation of the VPAC1/2 and PAC1 receptors. Specific agonists of VPAC2 or PAC1 decrease macrophage production of HIV-1, whereas sole activation of VPAC1 enhances viral growth. However, the combination of specific agonists mimicking the receptor preference of the natural neuropeptides reproduces the ability of VIP and PACAP to increase macrophage resistance to HIV-1 replication. VIP and PACAP up-regulated macrophage secretion of the beta-chemokines CCL3 and CCL5 and the cytokine IL-10, whose neutralization reversed the neuropeptide-induced inhibition of HIV-1 replication. Our results suggest that VIP and PACAP and the receptors VPAC2 and PAC1 could be used as targets for developing alternative therapeutic strategies for HIV-1 infection.

Engineering novel VPAC2-selective agonists with improved stability and glucose-lowering activity in vivo.[Pubmed:17110523]

J Pharmacol Exp Ther. 2007 Feb;320(2):900-6.

A previously described VPAC2-selective agonist, Bay 55-9837 (peptide HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY), had several limitations with respect to its potential as an insulin secretagogue for the treatment of type 2 diabetes. These limitations were primarily poor stability in aqueous buffer and short duration of action in vivo. In this report, we describe a series of novel analogs of Bay 55-9837 that were designed around the likely degradation mechanisms and structure-activity relationship of this peptide with a view to overcoming its limitations. These analogs were tested for improved liquid stability and retention of VPAC2-selective binding and activation, as well as prolonged activity in vivo. Although several degradation mechanisms were possible based on the degradation pattern, it was determined that deamidation at the two asparagines (N9 and N28) was the major instability determinant. Changing these two asparagines to glutamines did not negatively affect VPAC2-selective binding and activation. The double glutamine mutein analog, BAY(Q9Q28), retained full VPAC2 activity and selectivity while displaying no significant degradation when stored at 40 degrees C for 4 weeks. This is in contrast to Bay 55-9837, which showed greater than 80% degradation when stored at 40 degrees C for 2 weeks. A cysteine was added to the C terminus of BAY(Q9Q28), followed by site-specific cysteine conjugation with a 22- or 43-kDa polyethylene glycol (PEG) to yield BAY(Q9Q28C32)PEG22 or BAY(Q9Q28C32)PEG43, respectively. These PEGylated peptides retain the ability to selectively bind and activate the VPAC2 receptor and have prolonged glucose-lowering activity in vivo.

Engineering of a VPAC2 receptor peptide agonist to impart dipeptidyl peptidase IV stability and enhance in vivo glucose disposal.[Pubmed:17149884]

J Med Chem. 2006 Dec 14;49(25):7545-8.

VPAC2P-PEG is a VPAC2 receptor agonist peptide that acts as a glucose-dependent insulin secretagogue. Proteolysis by DPPIV may contribute to the in vivo clearance of VPAC2P-PEG. Here, the N-terminus of VPAC2P-PEG is modified by N-terminal acetylation to impart DPPIV resistance. The acetylated peptide, Ac-VPAC2P-PEG, is a selective and potent VPAC2 agonist, resistant to DPPIV proteolysis, and exhibits substantially improved half-life and glucose disposal in rodents. Ac-VPAC2P-PEG has therapeutic potential for diabetes management.

A potent and highly selective VPAC2 agonist enhances glucose-induced insulin release and glucose disposal: a potential therapy for type 2 diabetes.[Pubmed:11978642]

Diabetes. 2002 May;51(5):1453-60.

Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) activate two shared receptors, VPAC1 and VPAC2. Activation of VPAC1 has been implicated in elevating glucose output, whereas activation of VPAC2 may be involved in insulin secretion. A hypothesis that a VPAC2-selective agonist would enhance glucose disposal by stimulating insulin secretion without causing increased hepatic glucose production was tested using a novel selective agonist of VPAC2. This agonist, Bay 55-9837, was generated through site-directed mutagenesis based on sequence alignments of PACAP, VIP, and related analogs. The peptide bound to VPAC2 with a dissociation constant (K(d)) of 0.65 nmol/l and displayed >100-fold selectivity over VPAC1. Bay 55-9837 stimulated glucose-dependent insulin secretion in isolated rat and human pancreatic islets, increased insulin synthesis in purified rat islets, and caused a dose-dependent increase in plasma insulin levels in fasted rats, with a half-maximal stimulatory concentration of 3 pmol/kg. Continuous intravenous or subcutaneous infusion of the peptide reduced the glucose area under the curve following an intraperitoneal glucose tolerance test. The peptide had effects on intestinal water retention and mean arterial blood pressure in rats, but only at much higher doses. Bay 55-9837 may be a useful therapy for the treatment of type 2 diabetes.