The Long-Acting Vasoactive Intestinal Polypeptide Agonist RO 25-1553 Is Highly Selective of the VIP 2 Receptor Subclass

Gourlet, Philippe; Vertongen, Pascale; Vandermeers, André; Vandermeers‐Piret, Marie‐Claire; Rathé, Jean; Neef, Philippe De; Waelbroeck, Magalì; Robberecht, Patrick

doi:10.1016/s0196-9781(96)00322-1

Cited by 142 publications

(104 citation statements)

References 24 publications

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“…VIP analoging based on this structural information and alanine scanning (27) has been directed toward improving peptide stability and potency in BAL fluid for the treatment of asthma (21). Two of these analogs, Ro 25-1392 and Ro 25-1553, were later shown to be VPAC2 selective agonists (18,20). As a therapeutic agent, however, the presence of N-terminal acylation, cyclization from Lys-21 to Asp-25, C-terminal amidation, and O-Me-Tyr-10 or Nle-17 on these analogs (see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The only available VPAC2 selective agonists are two cyclized synthetic analogs of VIP (18,20). To determine whether a recombinant VPAC2-selective peptide can be made, the four chemical modifications of one of them, Ro 25-1553 (21), were sequentially removed and tested in radioligand competition binding and cAMP activation assay (see Table I, R3P1 to R3P3).…”

Section: Vpac2 Selective Agonist Can Be a Recombinant Peptide (Round mentioning

confidence: 99%

“…VIP chemical analogs Ro 25-1553 and Ro 25-1392 have been reported as VPAC2 selective agonists (18,20), but they were not designed to be selective for VPAC2 so that VPAC2 selective determinants were not known (21). In the current work, we have taken a systematic approach to identify the minimal VPAC2 selective determinants necessary to confer maximal VPAC2 selectivity.…”

Section: Figmentioning

confidence: 99%

“…In the current study, we have developed an efficient recombinant expression system that can produce peptides without any exogenous amino acids. This has allowed us to perform an extensive structure-activity relationship study of PACAP, VIP, and a VPAC2 selective analog (18) and we report the first recombinant production of VPAC2 selective agonists.…”

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confidence: 99%

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Generation of Highly Selective VPAC2 Receptor Agonists by High Throughput Mutagenesis of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Peptide

Yung¹,

Cruz

Hamren³

et al. 2003

Journal of Biological Chemistry

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Pituitaryadenylate cyclase-activating peptide (PACAP) has a specific receptor PAC1 and shares two receptors VPAC1 and VPAC2 with vasoactive intestinal peptide (VIP). VPAC2 activation enhances glucose-induced insulin release while VPAC1 activation elevates glucose output. To generate a large pool of VPAC2 selective agonists for the treatment of type 2 diabetes, structure-activity relationship studies were performed on PACAP, VIP, and a VPAC2 selective VIP analog. Chemical modifications on this analog that prevent recombinant expression were sequentially removed to show that a recombinant peptide would retain VPAC2 selectivity. An efficient recombinant expression system was then developed to produce and screen hundreds of mutant peptides. The 11 mutations found on the VIP analog were systematically replaced with VIP or PACAP sequences. Three of these mutations, V19A, L27K, and N28K, were sufficient to provide most of the VPAC2 selectivity. C-terminal extension with the KRY sequence from PACAP38 led to potent VPAC2 agonists with improved selectivity (100 -1000-fold). Saturation mutagenesis at positions 19, 27, 29, and 30 of VIP and chargescanning mutagenesis of PACAP27 generated additional VPAC2 selective agonists. We have generated the first set of recombinant VPAC2 selective agonists described, which exhibit activity profiles that suggest therapeutic utility in the treatment of diabetes.Pituitary adenylate cyclase-activating polypeptide (PACAP), 1 originally isolated from ovine hypothalamus (1) by following pituitary adenylate cyclase activation, belongs to the secretin/glucagon/vasoactive intestinal peptide (VIP) family of peptides (2). These peptides are expressed as part of larger proteins that are processed by proteolysis followed by Cterminal amidation to generate the mature amidated peptides (Fig. 1). PACAP exists as a 38-residue form (PACAP38), and as a shorter form corresponding to the N-terminal 27 amino acids of PACAP38 (PACAP27). Both forms of PACAP bind to and activate the G-protein-coupled receptors PAC1, VPAC1, and VPAC2, whereas the related 28-mer peptide VIP only recognizes VPAC1 and VPAC2 (3). Activation of multiple receptors by PACAP or VIP has broad physiological effects on nervous, endocrine, cardiovascular, reproductive, muscular, and immune systems (4). Thus, clinical applications will require selective activation of a particular receptor to minimize potential side effects mediated by the other receptors. For example, we have previously demonstrated that VPAC2 activation induces glucose-dependent insulin secretion without the undesired side effects mediated by VPAC1 such as watery diarrhea (5). Therefore, to provide a potential therapy for type 2 diabetes, VPAC2 selectivity is an absolute requirement.We sought to identify key determinants of VPAC2 selectivity and generate a peptide with the minimum number of mutations. However, structure-function relationship studies on VIP and PACAP (6 -15) have been restricted by the number of peptides that can be tested due to limitations of peptide synth...

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Section: Discussionmentioning

confidence: 99%

Section: Vpac2 Selective Agonist Can Be a Recombinant Peptide (Round mentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

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Generation of Highly Selective VPAC2 Receptor Agonists by High Throughput Mutagenesis of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Peptide

Yung¹,

Cruz

Hamren³

et al. 2003

Journal of Biological Chemistry

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“…Two deletion variants of maxadilan, M65 (Uchida et al, 1998) and max.d.4 (Moro et al, 1999) have been reported to be PAC1 receptor antagonists, but these peptides have not been extensively characterised. Ro251553 (Gourlet et al, 1997a(Gourlet et al, , 1997b Ro251392 (Xia et al, 1997) Maxadilan (Moro and Lerner, 1997) Selective antagonists PG97-269 (Gourlet et al, 1997a) …”

Section: Ensembl Id Ensg00000181408mentioning

confidence: 99%

Ligand-gated Ion Channels

Encyclopedic Reference of Molecular Pharmacology

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Vasoactive intestinal polypeptide receptor VPAC1 subtype is predominant in rat prostate membranes

1999

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The Long-Acting Vasoactive Intestinal Polypeptide Agonist RO 25-1553 Is Highly Selective of the VIP 2 Receptor Subclass

Cited by 142 publications

References 24 publications

Generation of Highly Selective VPAC2 Receptor Agonists by High Throughput Mutagenesis of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Peptide

Generation of Highly Selective VPAC2 Receptor Agonists by High Throughput Mutagenesis of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-activating Peptide

Ligand-gated Ion Channels

Vasoactive intestinal polypeptide receptor VPAC1 subtype is predominant in rat prostate membranes

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