Inhibition of influenza a virus infection by natural stilbene piceatannol targeting virus hemagglutinin.

BACKGROUND: Given the magnitude of influenza pandemics as a threat to the global population, it is crucial to have as many prevention and treatment options as possible. Piceatannol (PIC) is a tetrahydroxylated stilbenoid (trans-3,4,3',5'-tetrahydroxystilbene), also known as 3'- hydroxy resveratrol, which has demonstrated many different biological activities such as anti-inflammatory and antiviral activities. PURPOSE: In this study, the anti-influenza A virus (IAV) activities and mechanisms of PIC in vitro and in vivo were investigated in order to provide reference for the development of novel plant-derived anti-IAV drugs. METHODS: The viral plaque assay, RT-PCR and western blot assay were used to evaluate the anti-IAV effects of PIC in vitro. The anti-IAV mechanism of PIC was determined by HA syncytium assay, DARTS assay and Surface Plasmon Resonance assay. The mouse pneumonia model combined with HE staining were used to study the anti-IAV effects of PIC in vivo. RESULTS: PIC shows inhibition on the multiplication of both H1N1 and H3N2 viruses, and blocks the infection of H5N1 pseudovirus with low toxicity. PIC may directly act on the envelope of IAV to induce the rupture and inactivation of IAV particles. PIC can also block membrane fusion via binding to HA2 rather than HA1 and cleavage site of HA0. PIC may interact with the two residues (HA2-T68 and HA2-I75) of HA2 to block the conformational change of HA so as to inhibit membrane fusion. Importantly, oral therapy of PIC also markedly improved survival and reduced viral titers in IAV-infected mice. CONCLUSION: PIC possesses significant anti-IAV effects both in vitro and in vivo and may block IAV infection mainly through interaction with HA to block membrane fusion. Thus, PIC has the potential to be developed into a new broad-spectrum anti-influenza drug for the prevention and treatment of influenza.

The inhibition effects and mechanisms of sulfated chitooligosaccharides on influenza A virus in vitro and in vivo.

Sulfated chitooligosaccharide was reported to possess inhibition effect on human immunodeficiency virus (HIV) entry into host cells. Herein, we prepared chitooligosaccharide COS and its sulfate derivative SCOS and explored whether the sulfation modification can enhance the anti-influenza A virus (IAV) activity of COS. Interestingly, we discovered that SCOS possessed broad-spectrum anti-IAV effects with low toxicity, while the non-sulfated chitooligosaccharide COS had very low inhibition on IAV, verifying that the sulfation modification is essential for the anti-IAV actions of chitooligosaccharide. SCOS may target virus hemagglutinin (HA) protein to block both virus adsorption and membrane fusion processes. Oral administration of SCOS significantly decreased pulmonary viral titers and improved survival rate in IAV infected mice, comparable to the effects of Oseltamivir. Therefore, our findings support further studies on the use of SCOS as a novel entry inhibitor for IAV and as a supplement to current therapeutics for influenza.