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

• Published in: Nature communications Vol. 12; no. 1; pp. 2654 - 11
• Main Authors: Saito, Makoto, Itoh, Yasushi, Yasui, Fumihiko, Munakata, Tsubasa, Yamane, Daisuke, Ozawa, Makoto, Ito, Risa, Katoh, Takayuki, Ishigaki, Hirohito, Nakayama, Misako, Shichinohe, Shintaro, Yamaji, Kenzaburo, Yamamoto, Naoki, Ikejiri, Ai, Honda, Tomoko, Sanada, Takahiro, Sakoda, Yoshihiro, Kida, Hiroshi, Le, Thi Quynh Mai, Kawaoka, Yoshihiro, Ogasawara, Kazumasa, Tsukiyama-Kohara, Kyoko, Suga, Hiroaki, Kohara, Michinori
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326/596; 692/308/575; Adsorption; Animal models; Animals; Antibodies; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral drugs; Biomolecules; Disease Models, Animal; Dogs; Enzymatic activity; Exo-a-sialidase; Female; Functionals; HEK293 Cells; Hemagglutinin Glycoproteins, Influenza Virus - metabolism; Hemagglutinins; Humanities and Social Sciences; Humans; Infections; Influenza; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H1N1 Subtype - metabolism; Macaca fascicularis; Madin Darby Canine Kidney Cells; Membrane fusion; Mice; Mice, Inbred BALB C; Molecular Structure; multidisciplinary; Orthomyxoviridae; Orthomyxoviridae Infections - drug therapy; Oseltamivir; Peptides; Peptides - chemistry; Peptides - pharmacology; Pneumonia; Pneumonia - prevention & control; Primates; Proteins; Science; Science (multidisciplinary); Viral envelope proteins; Virus Replication - drug effects; Viruses; Zanamivir
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22964-w

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. Here, the authors report bi-functional, wide tropic macrocycles that bind the influenza viral envelope protein hemagglutinin and inhibit virus infection by blocking adsorption and fusion and show efficacy in preventing severe pneumonia at later stages of infection in mouse and non-human primate cynomolgus macaque models.