Generation of KS-133 as a Novel Bicyclic Peptide with a Potent and Selective VIPR2 Antagonist Activity that Counteracts Cognitive Decline in a Mouse Model of Psychiatric Disorders.

Kotaro Sakamoto,Satoshi Asano,Mei Yamada,Teruaki Masutani,Lu Chen,Nobumasa Hino,Tatsunori Miyaoka,Kenji Ishimoto,Shinsaku Nakagawa,Yukio Ago

doi:10.3389/fphar.2021.751587

Abstract

Worldwide, more than 20 million people suffer from schizophrenia, but effective and definitive new therapeutic drugs/treatments have not been established. Vasoactive intestinal peptide receptor 2 (VIPR2) might be an attractive drug target for the treatment of schizophrenia because both preclinical and clinical studies have demonstrated a strong link between high expression/overactivation of VIPR2 and schizophrenia. Nevertheless, VIPR2-targeting drugs are not yet available. VIPR2 is a class-B G protein-coupled receptor that possesses high structural homology to its subtypes, vasoactive intestinal peptide receptor 1 (VIPR1) and pituitary adenylate cyclase-activating polypeptide type-1 receptor (PAC1). These biological and structural properties have made it difficult to discover small molecule drugs against VIPR2. In 2018, cyclic peptide VIpep-3, a VIPR2-selective antagonist, was reported. The aim of this study was to generate a VIpep-3 derivative for in vivo experiments. After amino acid substitution and structure optimization, we successfully generated KS-133 with 1) a VIPR2-selective and potent antagonistic activity, 2) at least 24 h of stability in plasma, and 3) in vivo pharmacological efficacies in a mouse model of psychiatric disorders through early postnatal activation of VIPR2. To the best of our knowledge, this is the first report of a VIPR2-selective antagonistic peptide that counteracts cognitive decline, a central feature of schizophrenia. KS-133 may contribute to studies and development of novel schizophrenia therapeutic drugs that target VIPR2.

Highlights

Vasoactive intestinal peptide receptor (VIPR) 2, known as VPAC2, is a class-B G protein-coupled receptor (GPCR) encoded by the VIPR2 gene
VIPR2 antagonist activity was improved in the Gq/calcium signaling pathway, even though the molecular weight was reduced from VIpep-3 (1941.1 g/mol) to KS-133 (1558.8 g/mol)
KS-133 is active in vivo, inhibiting VIPR2mediated cAMP-response element-binding protein (CREB) activation and preventing cognitive impairment in a pharmacological model of early postnatal VIPR2 overactivation, a relevant mouse model of schizophrenia (Ago et al, 2015; Ago et al, 2021)

Summary

Introduction

Vasoactive intestinal peptide receptor (VIPR) 2, known as VPAC2, is a class-B G protein-coupled receptor (GPCR) encoded by the VIPR2 gene. Tian et al (2019) developed a conditional human VIPR2 bacterial artificial chromosome transgenic mouse model of VIPR2 copy number variation (CNV) This mouse model shows cognitive, sensorimotor gating, and social behavioral deficits and decreased complexity of dendritic arborization of striatal spiny projection neurons. We found that VIPR2-deficient mice exhibit a selective deficit in fear extinction and abnormal dendritic morphology of prefrontal cortex neurons (Ago et al, 2017) These findings suggest that VIPR2 plays an important role in the regulation of dendritic morphology and that the VIPR2 link to mental health disorders may be due in part to overactive VIPR2 signaling at a time when neural circuits involved in cognition and social behavior are being established. A significant potential exists for the development of therapeutics that target this receptor

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