Discovery of artificial VIPR2-antagonist peptides possessing receptor- and ligand-selectivity

Sakamoto, Kotaro; Koyama, Ryokichi; Kamada, Yusuke; Miwa, Masanori; Tani, Akiko

doi:10.1016/j.bbrc.2018.07.144

Cited by 15 publications

(14 citation statements)

References 18 publications

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“…Structure-guided design may therefore enable peptides drugs to selectively distinguish between and modulate the action of two endogenous peptides that act at the same receptor, one of which causes a detrimental pathophysiological action, perhaps owing to differences in spatial or temporal signalling. Strategies such as screening phage display peptides have also been effective in discovering novel peptide ligands; for example, antagonists of the class B VIP 2 receptor that have nanomolar affinity were identified using this approach 159 .…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Advances in therapeutic peptides targeting G protein-coupled receptors

Davenport

Scully

Graaf

et al. 2020

Nat Rev Drug Discov

194

197

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G protein-coupled receptors (GPCRs) mediate a wide range of signalling processes and are targeted by one third of the drugs in clinical use 1. Although most GPCR-targeting therapeutics are small molecules 2 , the endogenous ligands for many GPCRs are peptides (comprising 50 or fewer amino acids), which suggests that this class of molecule could be therapeutically useful. GPCRs are divided into families based on structural similarities. The largest group is the class A (rhodopsinlike) family, followed by the class B (secretin) family. Although other families exist, including class C and the frizzled and adhesion classes, therapeutics have predominantly targeted class A and B GPCRs, so this Review is focused on these two groups. The International Union of Basic and Clinical Pharmacology (IUPHAR) Guide to Pharmacology 3 currently lists 197 class A receptors with known ligands (excluding olfactory, vision, taste and vomeronasal sensory receptors), where 64 (32%) of these bind to endogenous peptides 3. In GPCR class B, there are 20 receptors activated by 15 endogenous peptides. These GPCRs are grouped in the following families, based on the ligand to which they bind: calcitonin, corticotropin-releasing factor, glucagon, parathyroid hormone (which is generally considered to be a peptide, despite its 84-amino-acid length), vasoactive intestinal peptide (VIP) or pituitary adenylate cyclase-activating peptide (PACAP).

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Section: Perspectives and Conclusionmentioning

confidence: 99%

Advances in therapeutic peptides targeting G protein-coupled receptors

Davenport

Scully

Graaf

et al. 2020

Nat Rev Drug Discov

194

197

View full text Add to dashboard Cite

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“…Regarding VPAC2, cyclic peptides have been demonstrated to be selective agonists, such as Ro25-1553 [65], Ro25-1392 [66], and some other peptides, such as BAY 55-9837 [67] Hexanoyl [A 19 ,K 27,28 ]VIP, rRBAYL [68], and LBT-3627 [63]. Only two VPAC2 selective antagonists have been described thus far: PG99-465 [69] and VIpep-3 [70]. Some of these approaches aim to identify more metabolically stable peptides [63] in order to ameliorate their in vivo administration.…”

Section: Ligandsmentioning

confidence: 99%

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

Martı́nez

Juarranz

Gutiérrez‐Cañas

et al. 2019

IJMS

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The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP’s discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.

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“…Secretin can bind VPAC1 and VPAC2 but with much lower affinity than SCTR. The described above findings explain difficulties in the pharmacology of class B GPCRs, e.g., lack of highly selective antagonist against VPAC2 and PAC1 receptors for many years [30,31].…”

Section: Resultsmentioning

confidence: 99%

“…Slightly more data are available regarding peptide analogs of VIP and PACAP interacting with VPAC receptors. There are known peptide antagonists and agonists of PAC1 and VPAC1 [52,53,54] and of VPAC2 [31,55,56] that were tested experimentally and a few peptide analogs with the VPAC1/VPAC2 selectivity confirmed experimentally [57]. Nevertheless, it was clearly demonstrated that the N-terminus of the peptides were essential for receptor activation and discrimination between peptidic agonists and antagonists.…”

Section: Resultsmentioning

confidence: 99%

A Molecular Dynamics Study of Vasoactive Intestinal Peptide Receptor 1 and the Basis of Its Therapeutic Antagonism

Latek

Langer

Krzyśko

et al. 2019

IJMS

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Vasoactive intestinal peptide receptor 1 (VPAC1) is a member of a secretin-like subfamily of G protein-coupled receptors. Its endogenous neuropeptide (VIP), secreted by neurons and immune cells, modulates various physiological functions such as exocrine and endocrine secretions, immune response, smooth muscles relaxation, vasodilation, and fetal development. As a drug target, VPAC1 has been selected for therapy of inflammatory diseases but drug discovery is still hampered by lack of its crystal structure. In this study we presented the homology model of this receptor constructed with the well-known web service GPCRM. The VPAC1 model is composed of extracellular and transmembrane domains that form a complex with an endogenous hormone VIP. Using the homology model of VPAC1 the mechanism of action of potential drug candidates for VPAC1 was described. Only two series of small-molecule antagonists of confirmed biological activity for VPAC1 have been described thus far. Molecular docking and a series of molecular dynamics simulations were performed to elucidate their binding to VPAC1 and resulting antagonist effect. The presented work provides the basis for the possible binding mode of VPAC1 antagonists and determinants of their molecular recognition in the context of other class B GPCRs. Until the crystal structure of VPAC1 will be released, the presented homology model of VPAC1 can serve as a scaffold for drug discovery studies and is available from the author upon request.

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Discovery of artificial VIPR2-antagonist peptides possessing receptor- and ligand-selectivity

Cited by 15 publications

References 18 publications

Advances in therapeutic peptides targeting G protein-coupled receptors

Advances in therapeutic peptides targeting G protein-coupled receptors

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

A Molecular Dynamics Study of Vasoactive Intestinal Peptide Receptor 1 and the Basis of Its Therapeutic Antagonism

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