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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.

SUBMITTER: Saito M

PROVIDER: S-EPMC8113231 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Saito Makoto M Itoh Yasushi Y Yasui Fumihiko F Munakata Tsubasa T Yamane Daisuke D Ozawa Makoto M Ito Risa R Katoh Takayuki T Ishigaki Hirohito H Nakayama Misako M Shichinohe Shintaro S Yamaji Kenzaburo K Yamamoto Naoki N Ikejiri Ai A Honda Tomoko T Sanada Takahiro T Sakoda Yoshihiro Y Kida Hiroshi H Le Thi Quynh Mai TQM Kawaoka Yoshihiro Y Ogasawara Kazumasa K Tsukiyama-Kohara Kyoko K Suga Hiroaki H Kohara Michinori M

Nature communications 20210511 1

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 Grou ...[more]

PMID: 33976181

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Project description:BackgroundWith the emergence of new influenza virus strains that are resistant to current inhibitors such as oseltamivir (anti-neuraminidase (NA)) and amantadine (anti-M2 proton channel), influenza A viruses continue to be a serious threat to the public health worldwide. With this in view, there is a persistent need for the development of broader and more effective vaccines and therapeutics. Identification of broadly neutralizing antibodies (bNAbs) that recognize relatively invariant structures ‎on influenza haemagglutinin (HA) stem has invigorated efforts to develop universal influenza vaccines.AimThe current computational study is designed to identify potential flavonoid inhibitors that bind to the contact epitopes of HA stem that are targeted by broadly neutralizing antibodies (bNAb).MethodIn this study, we utilized the three-dimensional crystallographic structure of different HA subtypes (H1, H2, H5, H3, and H7) in complex with bNAb to screen for potential broadly reactive influenza inhibitors. We performed Quantitative Structure-Activity and Relationship (QSAR) for 100 natural compounds known for their antiviral activity and performed molecular docking using AutoDock 4.2 suite. Furthermore, we conducted virtual screening of 1413 bioassay hit compounds by using virtual lab bench CLC Drug Discovery.ResultsThe results showed 18 lead flavonoids with strong binding abilities to bNAb epitopes of various HA subtypes. These 18 broadly reactive compounds exhibited significant interactions with an average of seven Hbonds, docking energy of -22.43 kcal·mol-1, and minimum interaction ‎ energy of -4.65 kcal·mol-1, with functional contact residues. Procyanidin depicted strong interactions with group 1 HAs, whereas both sorbitol and procyanidin exhibited significant interactions with group 2 HAs.ConclusionUsing in silico docking analysis, we identified 18 bioactive flavonoids with potential strong binding cababilities to influenza HA-stems of various subtypes, which are the target for bNAb. The virtual screened bioassay hit compounds depicted a high number of Hbonds but low interaction and docking values compared to antiviral flavonoids. Using structure-based design and nanotechnology-based approaches, identified molecules could be modified to generate next generation anti-influenza drugs.

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

Publications

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

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