Macrocyclic peptides exhibit antiviral effects against influenza virus HA and prevent pneumonia in animal models

Makoto Saito, Yasushi Itoh, Fumihiko Yasui, Tsubasa Munakata, Daisuke Yamane, Makoto Ozawa, Risa Ito, Takayuki Katoh, Hirohito Ishigaki, Misako Nakayama, Shintaro Shichinohe, Kenzaburo Yamaji, Naoki Yamamoto, Ai Ikejiri, Tomoko Honda, Takahiro Sanada, Yoshihiro Sakoda, Hiroshi Kida, Thi Quynh Mai Le, Yoshihiro Kawaoka, Kazumasa Ogasawara, Kyoko Tsukiyama-Kohara (), Hiroaki Suga () and Michinori Kohara ()
Additional contact information
Makoto Saito: Tokyo Metropolitan Institute of Medical Science
Yasushi Itoh: Shiga University of Medical Science, Setatsukinowa
Fumihiko Yasui: Tokyo Metropolitan Institute of Medical Science
Tsubasa Munakata: Tokyo Metropolitan Institute of Medical Science
Daisuke Yamane: Tokyo Metropolitan Institute of Medical Science
Makoto Ozawa: Kagoshima University
Risa Ito: The University of Tokyo
Takayuki Katoh: The University of Tokyo
Hirohito Ishigaki: Shiga University of Medical Science, Setatsukinowa
Misako Nakayama: Shiga University of Medical Science, Setatsukinowa
Shintaro Shichinohe: Shiga University of Medical Science, Setatsukinowa
Kenzaburo Yamaji: Tokyo Metropolitan Institute of Medical Science
Naoki Yamamoto: Tokyo Metropolitan Institute of Medical Science
Ai Ikejiri: Tokyo Metropolitan Institute of Medical Science
Tomoko Honda: Tokyo Metropolitan Institute of Medical Science
Takahiro Sanada: Tokyo Metropolitan Institute of Medical Science
Yoshihiro Sakoda: Hokkaido University
Hiroshi Kida: Hokkaido University Research Center for Zoonosis Control
Thi Quynh Mai Le: National Institute of Hygiene and Epidemiology
Yoshihiro Kawaoka: The University of Tokyo
Kazumasa Ogasawara: Shiga University of Medical Science, Setatsukinowa
Kyoko Tsukiyama-Kohara: Kagoshima University
Hiroaki Suga: The University of Tokyo
Michinori Kohara: Tokyo Metropolitan Institute of Medical Science

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Most anti-influenza drugs currently used, such as oseltamivir and zanamivir, inhibit the enzymatic activity of neuraminidase. However, neuraminidase inhibitor-resistant viruses have already been identified from various influenza virus isolates. Here, we report the development of a class of macrocyclic peptides that bind the influenza viral envelope protein hemagglutinin, named iHA. Of 28 iHAs examined, iHA-24 and iHA-100 have inhibitory effects on the in vitro replication of a wide range of Group 1 influenza viruses. In particular, iHA-100 bifunctionally inhibits hemagglutinin-mediated adsorption and membrane fusion through binding to the stalk domain of hemagglutinin. Moreover, iHA-100 shows powerful efficacy in inhibiting the growth of highly pathogenic influenza viruses and preventing severe pneumonia at later stages of infection in mouse and non-human primate cynomolgus macaque models. This study shows the potential for developing cyclic peptides that can be produced more efficiently than antibodies and have multiple functions as next-generation, mid-sized biomolecules.

Date: 2021
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DOI: 10.1038/s41467-021-22964-w

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