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Nat Commun
. 2021 May 11;12(1):2654.
doi: 10.1038/s41467-021-22964-w.
Macrocyclic peptides exhibit antiviral effects against influenza virus HA and prevent pneumonia in animal models
Makoto Saito # 1 , Yasushi Itoh # 2 , Fumihiko Yasui # 1 , Tsubasa Munakata 1 , Daisuke Yamane 1 , Makoto Ozawa 3 , Risa Ito 4 , Takayuki Katoh 4 , Hirohito Ishigaki 2 , Misako Nakayama 2 , Shintaro Shichinohe 2 , Kenzaburo Yamaji 1 , Naoki Yamamoto 1 , Ai Ikejiri 1 , Tomoko Honda 1 , Takahiro Sanada 1 , Yoshihiro Sakoda 5 , Hiroshi Kida 6 , Thi Quynh Mai Le 7 , Yoshihiro Kawaoka 8 , Kazumasa Ogasawara 2 , Kyoko Tsukiyama-Kohara 9 , Hiroaki Suga 10 , Michinori Kohara 11
Affiliations
- PMID: 33976181
- DOI: 10.1038/s41467-021-22964-w
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.