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

doi:10.3389/fphar.2021.751587

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

Front Pharmacol. 2021 Nov 4:12:751587. doi: 10.3389/fphar.2021.751587. eCollection 2021.

Authors

Kotaro Sakamoto¹, Lu Chen², Tatsunori Miyaoka², Mei Yamada², Teruaki Masutani¹, Kenji Ishimoto^{2

3

4}, Nobumasa Hino², Shinsaku Nakagawa^{2

3

4}, Satoshi Asano⁵, Yukio Ago^{2

3

4

5}

Affiliations

¹ Research and Development Department, Ichimaru Pharcos Company Limited, Gifu, Japan.
² Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
³ Laboratory of Innovative Food Science, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
⁴ Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan.
⁵ Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

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.

Keywords: KS-133; VIPR2/VPAC2; antagonist; bicyclization; cyclic peptide; schizophrenia.