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3D-quantitative structure-activity relationship and antiviral effects of curcumin derivatives as potent inhibitors of influenza H1N1 neuraminidase.

ABSTRACT: Curcumin derivatives have been shown to inhibit replication of human influenza A viruses (IAVs). However, it is not clear whether curcumin and its derivatives can inhibit neuraminidase (NA) of influenza virus. In this study, a meaningful 3D quantitative structure-activity relationship model (comparative molecular field analysis R2?=?0.997, q2?=?0.527, s?=?0.064, F?=?282.663) was built to understand the chemical-biological interactions between their activities and neuraminidase. Molecular docking was used to predict binding models between curcumin derivatives and neuraminidase. Real-time polymerase chain reactions showed that the five active curcumin derivatives might have direct effects on viral particle infectivity in H1N1-infected lung epithelial (MDCK) cells. Neuraminidase activation assay showed that five active curcumin derivatives decreased H1N1-induced neuraminidase activation in MDCK cells. Indirect immunofluorescence assay indicated that two active curcumin derivatives (tetramethylcurcumin and curcumin) down-regulated the nucleoprotein expression. Curcumin inhibited IAV in vivo. The therapeutic mechanism of curcumin in the treatment of influenza viral pneumonia is related to improving the immune function of infected mice and regulating secretion of tumor necrosis-?, interleukin-6, and interferon-?. These results indicate that curcumin derivatives inhibit IAV by blocking neuraminidase in the cellular model and curcumin also has anti-IAV activity in the animal model.

SUBMITTER: Lai Y

PROVIDER: S-EPMC7125423 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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3D-quantitative structure-activity relationship and antiviral effects of curcumin derivatives as potent inhibitors of influenza H1N1 neuraminidase.

Lai Yanni Y Yan Yiwen Y Liao Shanghui S Li Yun Y Ye Yi Y Liu Ni N Zhao Fang F Xu Peiping P

Archives of pharmacal research 20200404 5

Curcumin derivatives have been shown to inhibit replication of human influenza A viruses (IAVs). However, it is not clear whether curcumin and its derivatives can inhibit neuraminidase (NA) of influenza virus. In this study, a meaningful 3D quantitative structure-activity relationship model (comparative molecular field analysis R<sup>2</sup> = 0.997, q<sup>2</sup> = 0.527, s = 0.064, F = 282.663) was built to understand the chemical-biological interactions between their activities and neuraminid ...[more]

PMID: 32248350

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Project description:In this paper, a novel natural influenza A H1N1 virus neuraminidase (NA) inhibitory peptide derived from cod skin hydrolysates was purified and its antiviral mechanism was explored. From the hydrolysates, novel efficient NA-inhibitory peptides were purified by a sequential approach utilizing an ultrafiltration membrane (5000 Da), sephadex G-15 gel column and reverse-phase high-performance liquid chromatography (RP-HPLC). The amino acid sequence of the pure peptide was determined by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) was PGEKGPSGEAGTAGPPGTPGPQGL, with a molecular weight of 2163 Da. The analysis of the Lineweacer?Burk model indicated that the peptide was a competitive NA inhibitor with Ki of 0.29 mM and could directly bind free enzymes. In addition, docking studies suggested that hydrogen binding might be the driving force for the binding affinity of PGEKGPSGEAGTAGPPGTPGPQGL to NA. The cytopathic effect reduction assay showed that the peptide PGEKGPSGEAGTAGPPGTPGPQGL protected Madin?Darby canine kidney (MDCK) cells from viral infection and reduced the viral production in a dose-dependent manner. The EC50 value was 471 ± 12 ?g/mL against H1N1. Time-course analysis showed that PGEKGPSGEAGTAGPPGTPGPQGL inhibited influenza virus in the early stage of the infectious cycle. The virus titers assay indicated that the NA-inhibitory peptide PGEKGPSGEAGTAGPPGTPGPQGL could directly affect the virus toxicity and adsorption by host cells, further proving that the peptide had an anti-viral effect with multiple target sites. The activity of NA-inhibitory peptide was almost inactivated during the simulated in vitro gastrointestinal digestion, suggesting that oral administration is not recommended. The peptide PGEKGPSGEAGTAGPPGTPGPQGL acts as a neuraminidase blocker to inhibit influenza A virus in MDCK cells. Thus, the peptide PGEKGPSGEAGTAGPPGTPGPQGL has potential utility in the treatment of the influenza virus infection.

Dataset Information

3D-quantitative structure-activity relationship and antiviral effects of curcumin derivatives as potent inhibitors of influenza H1N1 neuraminidase.

Publications

3D-quantitative structure-activity relationship and antiviral effects of curcumin derivatives as potent inhibitors of influenza H1N1 neuraminidase.

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