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

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.

• Authors: 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, Michinori Kohara
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 2654 (05 11 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33976181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Hemagglutinin Glycoproteins, Influenza Virus
• Peptides

Topics

• Animals
• Antiviral Agents (chemistry, pharmacology)
• Disease Models, Animal
• Dogs
• Female
• HEK293 Cells
• Hemagglutinin Glycoproteins, Influenza Virus (metabolism)
• Humans
• Influenza A Virus, H1N1 Subtype (drug effects, metabolism)
• Macaca fascicularis
• Madin Darby Canine Kidney Cells
• Mice, Inbred BALB C
• Molecular Structure
• Orthomyxoviridae Infections (drug therapy)
• Peptides (chemistry, pharmacology)
• Pneumonia (prevention & control)
• Virus Replication (drug effects)
• Mice