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

Makoto Saito,Takayuki Katoh,Thi Quynh Mai Le,Shintaro Shichinohe,Rieko Ito ,Toshiaki Munakata ,Kunio Ogasawara ,Fumihiko Yasui,Kyoko Tsukiyama-Kohara,Hirohito Ishigaki,Yasushi Itoh,Hiroaki Suga,Misako Nakayama,Yoshihiro Sakoda,Yoshihiro Kawaoka,Kenzaburo Yamaji,Takahiro Sanada,Daisuke Yamane,Hiroshi Kida,Ai Ikejiri,Makoto Ozawa,Naoki Yamamoto,Tomoko Honda,Michinori Kohara

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.

Highlights

Most anti-influenza drugs currently used, such as oseltamivir and zanamivir, inhibit the enzymatic activity of neuraminidase
Neuraminidase (NA) inhibitors are globally approved for influenza treatment, NA inhibitor-resistant viruses have already been isolated among seasonal H1N13,4, pandemic (H1N1) 20095–7, and even highly pathogenic avian H5N18,9 viruses
We further evaluated the in vivo efficacy of inhibitor of HA (iHA)-100 against influenza virus infection in a non-human primate cynomolgus macaque infection model (Fig. 4)

Summary

Introduction

Most anti-influenza drugs currently used, such as oseltamivir and zanamivir, inhibit the enzymatic activity of neuraminidase. 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. To devise smaller molecules capable of binding to influenza viral HA as potential antiviral agents[14] (Supplementary Fig. 1a), we use the RaPID system to obtain HA-targeting macrocycles, named iHAs. Among candidate iHAs, iHA-24 and iHA100 show inhibitory effects on the in vitro replication of a wide range of Group 1 influenza viruses. IHA-100 exhibits efficacy in inhibiting virus growth and preventing severe pneumonia at later stages of infection in mouse and non-human primate cynomolgus macaque models

Methods

Results

Conclusion