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

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.

Vasoactive intestinal peptide–VIPR2 signaling regulates tumor cell migration

“…In line with the effects of VIPR2 -silencing, the migration speed was higher in VIPR2-EGFP-expressing MCF-7 cells than that in EGFP-expressing cells ( Figure S4C ). Notably, treatment with KS-133, a potent and selective VIPR2 antagonist ( 35 ), dose-dependently inhibited VIP-induced cell migration in VIPR2-overexpressing MDA-MB-231 cells ( Figure 3D ). These results suggest that VIPR2 mediates cell migration induced by VIP.…”

“…Human VIPR2 -siRNAs (si1, 3024813653-000080 and -000090; si2, 3024813653-000020 and -000030; si3, 3024813653-000050 and -000060) were purchased from Sigma-Aldrich (St. Louis, MO, USA). A VIPR2-selective antagonistic peptide KS-133 was synthesized at SCRUM Inc. (Tokyo, Japan) as previously reported ( 35 ).…”

The VIPR2-selective antagonist KS-133 changes macrophage polarization and exerts potent anti-tumor effects as a single agent and in combination with an anti-PD-1 antibody

“…VIP–VIPR2 signaling has attracted attention as a drug target in the fields of central nervous system diseases, oncology, and immunity. In 2021, we generated 13-mer bicyclic peptide KS-133 as a potent and selective antagonist to VIPR2 [ 1 ]. KS-133 is resistant to protease degradation, suppresses the phosphorylation of CREB (a downstream signal of VIPR2) in brain tissues and exerts pharmacological effects in a mouse model of psychiatric disorders [ 1 ].…”

“…In 2021, we generated 13-mer bicyclic peptide KS-133 as a potent and selective antagonist to VIPR2 [ 1 ]. KS-133 is resistant to protease degradation, suppresses the phosphorylation of CREB (a downstream signal of VIPR2) in brain tissues and exerts pharmacological effects in a mouse model of psychiatric disorders [ 1 ]. Several lines of evidence support associations of VIPR2 with cancer and immunity.…”

Generation of KS-487 as a novel LRP1-binding cyclic peptide with higher affinity, higher stability and BBB permeability

“…Although most drug discoveries for CNS diseases have been made with low-molecular-weight compounds, there are some concerns that small molecules could have undesirable off-target effects due to limited drug target-selectivity and that modulating protein-protein interactions is difficult with conventional small molecules [ 5 ]. In contrast, medium-size molecules (such as a peptide) and macromolecules (such as an antibody) are superior to have drug target-selectivity and to modulate protein-protein interactions compared to small molecules [ [6] , [7] , [8] ], but the presence of BBB makes it extremely difficult for these molecules to enter the brain passively through peripheral administrations. Thus, the establishment of a technology to transport medium-size molecules and macromolecules to CNS is eagerly awaited.…”