2018 Fiscal Year Final Research Report

iHA-100 exhibited a high efficacy whether administered during the early phase or late phase of H5N1 infection

Research Project

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Project/Area Number	15H04739
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Research Field	Virology
Research Institution	Tokyo Metropolitan Institute of Medical Science
Principal Investigator	KOHARA Michinori 公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 特任研究員 (10250218)
Co-Investigator(Kenkyū-buntansha)	齊藤誠公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 研究員 (20433021) 徳永優子公益財団法人東京都医学総合研究所, ゲノム医科学研究分野, 研究員 (80555011)
Research Collaborator	MUNAKTA Tsubasa IMAI Yumiko
Project Period (FY)	2015-04-01 – 2018-03-31
Keywords	ウイルス / 感染症 / 微生物 / 免疫学
Outline of Final Research Achievements	Most anti-influenza drugs currently used, such as oseltamivir and zanamivir, inhibit the enzymatic activity of neuraminidase (NA). NA inhibitor-resistant viruses, however, have already been isolated among seasonal H1N1, pandemic (H1N1) 2009, and even highly pathogenic avian H5N1 viruses. These resistant viruses can only be controlled by a new antiviral with a mechanism of action that is totally different from NA inhibition. The recent development of the Random non-standard Peptides Integrated Discovery (RaPID) system enables the identification of high-affinity ligands for a protein of interest from easily prepared libraries consisting of over a trillion macrocyclic peptides. Here we report bi-functional, tropic macrocycles that bind the influenza viral envelope protein hemagglutinin and inhibit virus infection by blocking adsorption and fusion. They showed powerful efficacy in preventing severe pneumonia at later stages of infection in mouse and non-primate cynomolgus macaque models.
Free Research Field	感染免疫学
Academic Significance and Societal Importance of the Research Achievements	次世代の抗体医薬として、従来抗体が結合し得ない抗原領域を認識することが可能な特殊環状ペプチドに着目した。H5N1インフルエンザウイルスHA蛋白質に対して結合する特殊環状ペプチドiHA100を創成し、マウスにおいてリレンザでは治療効果を示さない感染４日後および６日後からの投与においても治療効果を示した。さらに霊長類感染モデルとしてカニクイザルに高病原性H5N1インフルエンザ感染時の発症防御効果を検討したところ良好な結果が得られ、iHA100は新規インフルエンザ治療薬の可能性が示された。これらHAウイルス蛋白質の選択的な認識・排除機構を解明し、さらなる治療薬の最適化や治療法の確立につなげる。