3-Anhydro-6-hydroxy-ophiobolin A displays high in vitro and in vivo efficacy against influenza A virus infection

The emerging avian-origin H7N9 influenza A virus, which causes mild to lethal human respiratory disease, continues to circulate in China, posing a great threat to public health. Influenza NS1 protein plays a key role in counteracting host innate immune responses, allowing the virus to efficiently replicate in the host. In this study, we compared NS1 amino acid sequences of H7N9 influenza A virus with those of other strains, and determined NS1 protein variability within the H7N9 virus and then evaluated the impact of amino acid substitutions on ability of the NS1 proteins to inhibit host innate immunity. Interestingly, the amino acid residue S212 was identified to have a profound effect on the primary function of NS1, since S212P substitution disabled H7N9 NS1 in suppressing the host RIG-I-dependent interferon response, as well as the ability to promote the virus replication. In addition, we identified another amino acid residue, I178, serving as a key site to keep NS1 protein high steady-state levels. When the isoleucine was replaced by valine at 178 site (I178V mutation), NS1 of H7N9 underwent rapid degradation through proteasome pathway. Furthermore, we observed that P212S and V178I mutation in NS1 of PR8 virus enhanced virulence and promoted the virus replication in vivo. Together, these results indicate that residues I178 and S212 within H7N9 NS1 protein are critical for stability and functioning of the NS1 protein respectively, and may contribute to the enhanced pathogenicity of H7N9 influenza virus. Electronic supplementary material The online version of this article (10.1186/s13567-018-0594-y) contains supplementary material, which is available to authorized users.

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“…Plaque assay was performed as previously described [35, 36]. Briefly, MDCK cells were infected with serial dilutions of the viruses.…”

Section: Methodsmentioning

confidence: 99%

Identification of two residues within the NS1 of H7N9 influenza A virus that critically affect the protein stability and function

Wang

Zhang

et al. 2018

Vet Res

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“…Additionally, at the same low concentration, the generation of A549 cells was not influenced. In vivo experiment, comparing with the infected control group, 5 decreased the death, pulmonary lesions, splenic atrophy, and thymic atrophy of mice infected with WSN at 0.3 mg/kg, intranasal inoculation [ 22 ].…”

Section: Anti-influenza Activitymentioning

confidence: 99%

“…Additionally, MDR reversal effects of Ophs on multiple tumor cells with a low concentration were proven by both in vitro and in vivo experiments [ 20 , 21 ]. Furthermore, Ophs also possess anti-influenza [ 22 ] and inflammation-promoting activities [ 23 ]. With their diverse pharmacological properties, Ophs are shown to be a group of promising drug candidates.…”

Section: Introductionmentioning

confidence: 99%

The Biological Activities of Sesterterpenoid-Type Ophiobolins

2017

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Ophiobolins (Ophs) are a group of tricarbocyclic sesterterpenoids whose structures contain a tricyclic 5-8-5 carbotricyclic skeleton. Thus far, 49 natural Ophs have been reported and assigned into A–W subgroups in order of discovery. While these sesterterpenoids were first characterized as highly effective phytotoxins, later investigations demonstrated that they display a broad spectrum of biological and pharmacological characteristics such as phytotoxic, antimicrobial, nematocidal, cytotoxic, anti-influenza and inflammation-promoting activities. These bioactive molecules are promising drug candidates due to the developments of their anti-proliferative activities against a vast number of cancer cell lines, multidrug resistance (MDR) cells and cancer stem cells (CSCs). Despite numerous studies on the biological functions of Ophs, their pharmacological mechanism still requires further research. This review summarizes the chemical structures, sources, and biological activities of the oph family and discusses its mechanisms and structure–activity relationship to lay the foundation for the future developments and applications of these promising molecules.

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“…For example, the sea Verrucosispora is a rare actinomycetes that can secrete a variety of biologically active metabolites, such as Compounds 1–3, with a good inhibitory effect on H1N1 influenza virus [ 115 ]. In addition, Wang et al isolated a new sesterterpene called L435-3 from the phytopathogenic fungus Bipolaris oryzae and proved that L435-3 has strong antiviral activity against influenza, including against WSN and PR8 viruses [ 116 , 117 ]. L435-3 acts by inhibiting the replication of influenza virus through increasing the production of type III interferon and some interferon-stimulated genes (ISGs) in the host, thus enhancing the antiviral ability of the host [ 116 ].…”

Section: Development and Effects Of Influenza Antiviral Drugsmentioning

confidence: 99%

Development and Effects of Influenza Antiviral Drugs

et al. 2021

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Influenza virus is a highly contagious zoonotic respiratory disease that causes seasonal outbreaks each year and unpredictable pandemics occasionally with high morbidity and mortality rates, posing a great threat to public health worldwide. Besides the limited effect of vaccines, the problem is exacerbated by the lack of drugs with strong antiviral activity against all flu strains. Currently, there are two classes of antiviral drugs available that are chemosynthetic and approved against influenza A virus for prophylactic and therapeutic treatment, but the appearance of drug-resistant virus strains is a serious issue that strikes at the core of influenza control. There is therefore an urgent need to develop new antiviral drugs. Many reports have shown that the development of novel bioactive plant extracts and microbial extracts has significant advantages in influenza treatment. This paper comprehensively reviews the development and effects of chemosynthetic drugs, plant extracts, and microbial extracts with influenza antiviral activity, hoping to provide some references for novel antiviral drug design and promising alternative candidates for further anti-influenza drug development.

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3-Anhydro-6-hydroxy-ophiobolin A displays high in vitro and in vivo efficacy against influenza A virus infection

Cited by 8 publications

References 15 publications

Identification of two residues within the NS1 of H7N9 influenza A virus that critically affect the protein stability and function

Identification of two residues within the NS1 of H7N9 influenza A virus that critically affect the protein stability and function

The Biological Activities of Sesterterpenoid-Type Ophiobolins

Development and Effects of Influenza Antiviral Drugs

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