tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Yasushi Itoh[SUP] #[/SUP][SUP] 2 [/SUP], Fumihiko Yasui[SUP] #[/SUP][SUP] 1 [/SUP], Tsubasa Munakata[SUP] 1 [/SUP], Daisuke Yamane[SUP] 1 [/SUP], Makoto Ozawa[SUP] 3 [/SUP], Risa Ito[SUP] 4 [/SUP], Takayuki Katoh[SUP] 4 [/SUP], Hirohito Ishigaki[SUP] 2 [/SUP], Misako Nakayama[SUP] 2 [/SUP], Shintaro Shichinohe[SUP] 2 [/SUP], Kenzaburo Yamaji[SUP] 1 [/SUP], Naoki Yamamoto[SUP] 1 [/SUP], Ai Ikejiri[SUP] 1 [/SUP], Tomoko Honda[SUP] 1 [/SUP], Takahiro Sanada[SUP] 1 [/SUP], Yoshihiro Sakoda[SUP] 5 [/SUP], Hiroshi Kida[SUP] 6 [/SUP], Thi Quynh Mai Le[SUP] 7 [/SUP], Yoshihiro Kawaoka[SUP] 8 [/SUP], Kazumasa Ogasawara[SUP] 2 [/SUP], Kyoko Tsukiyama-Kohara[SUP] 9 [/SUP], Hiroaki Suga[SUP] 10 [/SUP], Michinori Kohara[SUP] 11 [/SUP]
Affiliations
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.
. 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[SUP] #[/SUP][SUP] 1 [/SUP], Yasushi Itoh[SUP] #[/SUP][SUP] 2 [/SUP], Fumihiko Yasui[SUP] #[/SUP][SUP] 1 [/SUP], Tsubasa Munakata[SUP] 1 [/SUP], Daisuke Yamane[SUP] 1 [/SUP], Makoto Ozawa[SUP] 3 [/SUP], Risa Ito[SUP] 4 [/SUP], Takayuki Katoh[SUP] 4 [/SUP], Hirohito Ishigaki[SUP] 2 [/SUP], Misako Nakayama[SUP] 2 [/SUP], Shintaro Shichinohe[SUP] 2 [/SUP], Kenzaburo Yamaji[SUP] 1 [/SUP], Naoki Yamamoto[SUP] 1 [/SUP], Ai Ikejiri[SUP] 1 [/SUP], Tomoko Honda[SUP] 1 [/SUP], Takahiro Sanada[SUP] 1 [/SUP], Yoshihiro Sakoda[SUP] 5 [/SUP], Hiroshi Kida[SUP] 6 [/SUP], Thi Quynh Mai Le[SUP] 7 [/SUP], Yoshihiro Kawaoka[SUP] 8 [/SUP], Kazumasa Ogasawara[SUP] 2 [/SUP], Kyoko Tsukiyama-Kohara[SUP] 9 [/SUP], Hiroaki Suga[SUP] 10 [/SUP], Michinori Kohara[SUP] 11 [/SUP]
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.