New influenza A Virus Entry Inhibitors Derived from the Viral Fusion Peptides

Wu, Wenjiao; Dong, Lin; Shen, Xintian; Li, Fangfang; Fang, Yuxin; Li, Kaiqun; Xun, Tianrong; Yang, Guang; Yang, Jie; Liu, Shuwen; He, Jian

doi:10.1371/journal.pone.0138426

Cited by 21 publications

(16 citation statements)

References 31 publications

(39 reference statements)

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“…Considering the early inhibitory effect of PPa on IAV and the important role of the viral envelope lipid bilayer in mediating the entry of viruses 22 , we speculated whether the viral envelope lipids were the possible target of PPa. Initially, we investigated the ability of PPa to inhibit fusion by blocking the interaction between HA and lipids using the polykaryon formation inhibition assay 23 , as shown in Fig.…”

Section: Ppa Interacts With the Viral Envelope Lipid Bilayer To Blockmentioning

confidence: 99%

The seafood Musculus senhousei shows anti-influenza A virus activity by targeting virion envelope lipids

Chen

Yang

et al. 2020

Biochemical Pharmacology

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The seafood Musculus senhousei shows anti-influenza A virus activity by targeting virion envelope lipids, Biochemical Pharmacology (2020), doi: https://doi. AbstractMarine environments are known to be a new source of structurally diverse bioactive molecules. In this paper, we identified a porphyrin derivative of Pyropheophorbide a (PPa) from the mussel Musculus senhousei (M. senhousei) that showed broad anti-influenza A virus activity in vitro against a panel of influenza A viral strains. The analysis of the mechanism of action indicated that PPa functions in the early stage of virus infection by interacting with the lipid bilayer of the virion, resulting in an alteration of membrane-associated functions, thereby blocking the entry of enveloped viruses into host cells. In addition, the anti-influenza A virus activity of PPa was further assessed in mice infected with the influenza A virus. The survival rate and mean survival time of mice were apparently prolonged compared with the control group which was not treated with the drug. Therefore, PPa and its derivatives may represent lead compounds for controlling influenza A virus infection.Keywords: Marine food, Musculus senhousei, Pyropheophorbide a, Anti-influenza A virus activity, Enveloped virus. the H5N1 pseudo-typed virus screening approach, we identified the traditional Chinese seafood M. senhousei as showing a good inhibitory activity toward influenza A virus (IAV). The preliminary mechanistic study indicated that the antiviral activity of this food resulted from the inhibition of virus entry during early infection. We then investigated the bioactive components of this mussel using a bioassay-guided approach, from which a porphyrin derivative named pyropheophorbide a (PPa) that showed significant anti-IAV activity in vitro was isolated and identified, indicating a potential application of this molecule in the development of new antiviral agents.IAVs are enveloped viruses, and the viral envelopes are derived from portions of the host cell membranes and function to cover the capsids to protect the packaged viral genome 7 . In addition to the lipid bilayer, the viral envelope also contains viral glycoproteins, such as hemagglutinin (HA), neuraminidase (NA) and the viral M2 protein. These components, including lipid bilayers and associated proteins, play important roles in the process of viral infection 8,9 . As a result, they are viewed as promising tools for the development of new anti-influenza A drugs 10 .The HA glycoprotein consisting of two subunits, HA1 and HA2, is located on the surface of the envelope and is responsible for binding to receptor sites on the host membrane (HA1) and mediating the fusion between viral and host membranes (HA2).Following fusion, the viral genome is able to enter and subsequently infect the host cells 11 .The lipid bilayer is a major component of the IAV envelope. To date, a number of molecules targeting virion envelope lipids to interfere with the fusion of viral-host cellular membranes have been reported 12,13 . These molecul...

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Section: Ppa Interacts With the Viral Envelope Lipid Bilayer To Blockmentioning

confidence: 99%

The seafood Musculus senhousei shows anti-influenza A virus activity by targeting virion envelope lipids

Chen

Yang

et al. 2020

Biochemical Pharmacology

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“…The peptide HA-FP-O is the segment of HA2 of H1 subtype with the sequence of GLFGAIAGFI E NGW E GMI D G. It is a so called fusion peptide responsible for the membrane destabilization and fusion under acidic condition, thus playing an important role in virus entry into host cells 4 . In addition, we employed a positively charged derivative of HA-FP-O, named as HA-FP-1 with the sequence of GLFGAIAGFI K NGW K GMI K G, as a control to study whether this peptide has a similar effect 23 .…”

Section: Resultsmentioning

confidence: 99%

“… *The H1 subtype is used as the reference sequence for this table, and changes from the H1 reference sequence are underlined 23 . …”

Section: Figurementioning

confidence: 99%

A “building block” approach to the new influenza A virus entry inhibitors with reduced cellular toxicities

Dong

et al. 2016

Sci Rep

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Influenza A virus (IAV) is a severe worldwide threat to public health and economic development that results in the emergence of drug-resistant or highly virulent strains. Therefore, it is imperative to develop potent anti-IAV drugs with different modes of action to currently available drugs. Herein, we show a new class of antiviral peptides generated by conjugating two known short antiviral peptides: part-1 (named Jp with the sequence of ARLPR) and part-2 (named Hp with the sequence of KKWK). The new peptides were thus created by hybridization of these two domains at C- and N- termini, respectively. The anti-IAV screening results identified that C20-Jp-Hp was the most potent peptide with IC50 value of 0.53 μM against A/Puerto Rico/8/34 (H1N1) strain. Interestingly, these new peptides display lower toxicities toward mammalian cells and higher therapeutic indices than their prototypes. In addition, the mechanism of action of C20-Jp-Hp was extensively investigated.

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“…The first is direct competition with SA binding by blocking receptor sites of HA-A, either directly with small peptide molecules [229,230] or by neutralising antibodies targeted against HA-A subunits [231]. The second strategy involves interference of the HA-A conformational change necessary for viral fusion [232][233][234], thus preventing the subsequent release of viral RNA into host cells [235]. Preventing viral replication early in the infection cycle has proved to be a promising tactic in preventing and treating viral infections and may provide cross-protection of different viral strains [236].…”

Section: Sialic Acid (Sa) and Haemagglutinin A (Ha-a)mentioning

confidence: 99%

New therapeutic targets for the prevention of infectious acute exacerbations of COPD: role of epithelial adhesion molecules and inflammatory pathways

et al. 2019

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Chronic respiratory diseases are among the leading causes of mortality worldwide, with the major contributor, chronic obstructive pulmonary disease (COPD) accounting for approximately 3 million deaths annually. Frequent acute exacerbations (AEs) of COPD (AECOPD) drive clinical and functional decline in COPD and are associated with accelerated loss of lung function, increased mortality, decreased health-related quality of life and significant economic costs. Infections with a small subgroup of pathogens precipitate the majority of AEs and consequently constitute a significant comorbidity in COPD. However, current pharmacological interventions are ineffective in preventing infectious exacerbations and their treatment is compromised by the rapid development of antibiotic resistance. Thus, alternative preventative therapies need to be considered. Pathogen adherence to the pulmonary epithelium through host receptors is the prerequisite step for invasion and subsequent infection of surrounding structures. Thus, disruption of bacterial–host cell interactions with receptor antagonists or modulation of the ensuing inflammatory profile present attractive avenues for therapeutic development. This review explores key mediators of pathogen–host interactions that may offer new therapeutic targets with the potential to prevent viral/bacterial-mediated AECOPD. There are several conceptual and methodological hurdles hampering the development of new therapies that require further research and resolution.

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New influenza A Virus Entry Inhibitors Derived from the Viral Fusion Peptides

Cited by 21 publications

References 31 publications

The seafood Musculus senhousei shows anti-influenza A virus activity by targeting virion envelope lipids

The seafood Musculus senhousei shows anti-influenza A virus activity by targeting virion envelope lipids

A “building block” approach to the new influenza A virus entry inhibitors with reduced cellular toxicities

New therapeutic targets for the prevention of infectious acute exacerbations of COPD: role of epithelial adhesion molecules and inflammatory pathways

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