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
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 a...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:a48f0731bf1640b887ab23400b1a5cfb2021-11-08T09:23:54ZGeneration 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 Disorders1663-981210.3389/fphar.2021.751587https://doaj.org/article/a48f0731bf1640b887ab23400b1a5cfb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.751587/fullhttps://doaj.org/toc/1663-9812Worldwide, 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.Kotaro SakamotoLu ChenTatsunori MiyaokaMei YamadaTeruaki MasutaniKenji IshimotoKenji IshimotoKenji IshimotoNobumasa HinoShinsaku NakagawaShinsaku NakagawaShinsaku NakagawaSatoshi AsanoYukio AgoYukio AgoYukio AgoYukio AgoFrontiers Media S.A.articleKS-133VIPR2/VPAC2cyclic peptidebicyclizationantagonistschizophreniaTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021) |
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KS-133 VIPR2/VPAC2 cyclic peptide bicyclization antagonist schizophrenia Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
KS-133 VIPR2/VPAC2 cyclic peptide bicyclization antagonist schizophrenia Therapeutics. Pharmacology RM1-950 Kotaro Sakamoto Lu Chen Tatsunori Miyaoka Mei Yamada Teruaki Masutani Kenji Ishimoto Kenji Ishimoto Kenji Ishimoto Nobumasa Hino Shinsaku Nakagawa Shinsaku Nakagawa Shinsaku Nakagawa Satoshi Asano Yukio Ago Yukio Ago Yukio Ago Yukio Ago 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 |
| description |
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. |
| format |
article |
| author |
Kotaro Sakamoto Lu Chen Tatsunori Miyaoka Mei Yamada Teruaki Masutani Kenji Ishimoto Kenji Ishimoto Kenji Ishimoto Nobumasa Hino Shinsaku Nakagawa Shinsaku Nakagawa Shinsaku Nakagawa Satoshi Asano Yukio Ago Yukio Ago Yukio Ago Yukio Ago |
| author_facet |
Kotaro Sakamoto Lu Chen Tatsunori Miyaoka Mei Yamada Teruaki Masutani Kenji Ishimoto Kenji Ishimoto Kenji Ishimoto Nobumasa Hino Shinsaku Nakagawa Shinsaku Nakagawa Shinsaku Nakagawa Satoshi Asano Yukio Ago Yukio Ago Yukio Ago Yukio Ago |
| author_sort |
Kotaro Sakamoto |
| title |
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 |
| title_short |
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 |
| title_full |
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 |
| title_fullStr |
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 |
| title_full_unstemmed |
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 |
| title_sort |
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 |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/a48f0731bf1640b887ab23400b1a5cfb |
| work_keys_str_mv |
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