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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Makoto Saito & Yasushi Itoh & Fumihiko Yasui & Tsubasa Munakata & Daisuke Yamane & Makoto Ozawa & Risa Ito & Takayuki Katoh & Hirohito Ishigaki & Misako Nakayama & Shintaro Shichinohe & Kenzaburo Yama, 2021. "Macrocyclic peptides exhibit antiviral effects against influenza virus HA and prevent pneumonia in animal models," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22964-w
    DOI: 10.1038/s41467-021-22964-w
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