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

Saito, Makoto; Itoh, Yasushi; Yasui, Fumihiko; Munakata, Toshiaki; Yamane, Daisuke; Ozawa, Makoto; Ito, Rieko; 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, Kunio; Tsukiyama-Kohara, Kyoko; Suga, Hiroaki; Kohara, Michinori

doi:10.1038/s41467-021-22964-w

Cited by 26 publications

(28 citation statements)

References 24 publications

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“…A more recent study identified potent teMP ligands against influenza hemagglutinin and demonstrated that the peptides inhibited in vitro replication of a broad range of group 1 influenza viruses. 2 One of the teMPs (iHA-100), a 15-mer macrocycle bearing four N-methylated amino acids, exhibited high 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 (Figure 4c). These case studies illustrate high therapeutic potential of teMPs in vivo.…”

Section: Potential Of the Thioether-closed Macrocyclic Peptides Obtai...mentioning

confidence: 99%

“…Q. M.KawaokaY.OgasawaraK.Tsukiyama-KoharaK.SugaH.KoharaM. Saito, M. Itoh, Y. Yasui, F. Munakata, T. Yamane, D. Ozawa, M. Ito, R. Katoh, T. Ishigaki, H. Nakayama, M. Shichinohe, S. Yamaji, K. Yamamoto, N. Ikejiri, A. Honda, T. Sanada, T. Sakoda, Y. Kida, H. Le, T. Q. M. Kawaoka, Y. Ogasawara, K. Tsukiyama-Kohara, K. Suga, H. Kohara, M. Nat. Commun.2021122654 …”

Section: Key Referencesmentioning

confidence: 99%

“…Importantly, the administration of unmodified D4-2 to mice in combination with therapeutic anti-CD20 or anti-gp75 antibodies enhanced their inhibitory effect on tumor metastasis. A more recent study identified potent teMP ligands against influenza hemagglutinin and demonstrated that the peptides inhibited in vitro replication of a broad range of group 1 influenza viruses . One of the teMPs (iHA-100), a 15-mer macrocycle bearing four N-methylated amino acids, exhibited high 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 (Figure c).…”

Section: Discovery Of Thioether-closed Macrocyclic Peptide Ligands By...mentioning

confidence: 99%

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The RaPID Platform for the Discovery of Pseudo-Natural Macrocyclic Peptides

2021

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Conspectus Although macrocyclic peptides bearing exotic building blocks have proven their utility as pharmaceuticals, the sources of macrocyclic peptide drugs have been largely limited to mimetics of native peptides or natural product peptides. However, the recent emergence of technologies for discovering de novo bioactive peptides has led to their reconceptualization as a promising therapeutic modality. For the construction and screening of libraries of such macrocyclic peptides, our group has devised a platform to conduct affinity-based selection of massive libraries (>1012 unique sequences) of in vitro expressed macrocyclic peptides, which is referred to as the random nonstandard peptides integrated discovery (RaPID) system. The RaPID system integrates genetic code reprogramming using the FIT (flexible in vitro translation) system, which is largely facilitated by flexizymes (flexible tRNA-aminoacylating ribozymes), with mRNA display technology. We have demonstrated that the RaPID system enables rapid discovery of various de novo pseudo-natural peptide ligands for protein targets of interest. Many examples discussed in this Account prove that thioether-closed macrocyclic peptides (teMPs) obtained by the RaPID system generally exhibit remarkably high affinity and specificity, thereby potently inhibiting or activating a specific function(s) of the target. Moreover, such teMPs are used for a wide range of biochemical applications, for example, as crystallization chaperones for intractable transmembrane proteins and for in vivo recognition of specific cell types. Furthermore, recent studies demonstrate that some teMPs exhibit pharmacological activities in animal models and that even intracellular proteins can be inhibited by teMPs, illustrating the potential of this class of peptides as drug leads. Besides the ring-closing thioether linkage in the teMPs, genetic code reprogramming by the FIT system allows for incorporation of a variety of other exotic building blocks. For instance, diverse nonproteinogenic amino acids, hydroxy acids (ester linkage), amino carbothioic acid (thioamide linkage), and abiotic foldamer units have been successfully incorporated into ribosomally synthesized peptides. Despite such enormous successes in the conventional FIT system, multiple or consecutive incorporation of highly exotic amino acids, such as d- and β-amino acids, is yet challenging, and particularly the synthesis of peptides bearing non-carbonyl backbone structures remains a demanding task. To upgrade the RaPID system to the next generation, we have engaged in intensive manipulation of the FIT system to expand the structural diversity of peptides accessible by our in vitro biosynthesis strategy. Semilogical engineering of tRNA body sequences led to a new suppressor tRNA (tRNAPro1E2) capable of effectively recruiting translation factors, particularly EF-Tu and EF-P. The use of tRNAPro1E2 in the FIT system allows for not only single but also consecutive and multiple elongation of exotic amino acids, such as d-, β-, and γ-amino a...

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Section: Potential Of the Thioether-closed Macrocyclic Peptides Obtai...mentioning

confidence: 99%

Section: Key Referencesmentioning

confidence: 99%

Section: Discovery Of Thioether-closed Macrocyclic Peptide Ligands By...mentioning

confidence: 99%

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The RaPID Platform for the Discovery of Pseudo-Natural Macrocyclic Peptides

2021

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“…This system helps in the identification of high-affinity ligands for a protein of interest. Using the RaPID system, Saito et al [66] obtained macrocycles named iHAs that can bind influenza HA. Among these peptides, iHA-100 inhibits both viral adsorption (IC 50 = 0.036 µM) and membrane fusion (EC 50 = 0.07 µM) by interacting with the HA stalk domain.…”

Section: The Peptide Iha-100 Generated By a Macrocyclic Peptide Expre...mentioning

confidence: 99%

Inhibition of Viral Membrane Fusion by Peptides and Approaches to Peptide Design

2021

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Fusion of lipid-enveloped viruses with the cellular plasma membrane or the endosome membrane is mediated by viral envelope proteins that undergo large conformational changes following binding to receptors. The HIV-1 fusion protein gp41 undergoes a transition into a “six-helix bundle” after binding of the surface protein gp120 to the CD4 receptor and a co-receptor. Synthetic peptides that mimic part of this structure interfere with the formation of the helix structure and inhibit membrane fusion. This approach also works with the S spike protein of SARS-CoV-2. Here we review the peptide inhibitors of membrane fusion involved in infection by influenza virus, HIV-1, MERS and SARS coronaviruses, hepatitis viruses, paramyxoviruses, flaviviruses, herpesviruses and filoviruses. We also describe recent computational methods used for the identification of peptide sequences that can interact strongly with protein interfaces, with special emphasis on SARS-CoV-2, using the PePI-Covid19 database.

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“…The peptides were synthesized by Cellmano Biotech Limited (Hefei, Anhui, China). All peptides were assembled on Peptide Synthesizer SyroI (Biotage, Uppsala, Sweden) using the standard solid-phase peptide synthesis method as previously described [25,26]. The peptides were aliquot and stored in −80 • C until use.…”

Section: Virus Cell Lines and Peptidesmentioning

confidence: 99%

In Silico Structure-Based Design of Antiviral Peptides Targeting the Severe Fever with Thrombocytopenia Syndrome Virus Glycoprotein Gn

Yuan

Wen

Chik

et al. 2021

Viruses

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Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus in Asia that causes severe disease. Despite its clinical importance, treatment options for SFTSV infection remains limited. The SFTSV glycoprotein Gn plays a major role in mediating virus entry into host cells and is therefore a potential antiviral target. In this study, we employed an in silico structure-based strategy to design novel cyclic antiviral peptides that target the SFTSV glycoprotein Gn. Among the cyclic peptides, HKU-P1 potently neutralizes the SFTSV virion. Combinatorial treatment with HKU-P1 and the broad-spectrum viral RNA-dependent RNA polymerase inhibitor favipiravir exhibited synergistic antiviral effects in vitro. The in silico peptide design platform in this study may facilitate the generation of novel antiviral peptides for other emerging viruses.

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

Cited by 26 publications

References 24 publications

The RaPID Platform for the Discovery of Pseudo-Natural Macrocyclic Peptides

The RaPID Platform for the Discovery of Pseudo-Natural Macrocyclic Peptides

Inhibition of Viral Membrane Fusion by Peptides and Approaches to Peptide Design

In Silico Structure-Based Design of Antiviral Peptides Targeting the Severe Fever with Thrombocytopenia Syndrome Virus Glycoprotein Gn

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