Abstract
The H1N1 influenza A virus of swine-origin caused pandemics throughout the world in 2009 and the highly pathogenic H5N1 avian influenza virus has also caused epidemics in Southeast Asia in recent years. The threat of influenza A thus remains a serious global health issue and novel drugs that target these viruses are highly desirable. Influenza A possesses an endonuclease within its RNA polymerase which comprises PA, PB1 and PB2 subunits. To identify potential new anti-influenza compounds in our current study, we screened 33 different types of phytochemicals using a PA endonuclease inhibition assay in vitro and an anti-influenza A virus assay. The marchantins are macrocyclic bisbibenzyls found in liverworts, and plagiochin A and perrottetin F are marchantin-related phytochemicals. We found from our screen that marchantin A, B, E, plagiochin A and perrottetin F inhibit influenza PA endonuclease activity in vitro. These compounds have a 3,4-dihydroxyphenethyl group in common, indicating the importance of this moiety for the inhibition of PA endonuclease. Docking simulations of marchantin E with PA endonuclease suggest a putative “fitting and chelating model” as the mechanism underlying PA endonuclease inhibition. The docking amino acids are well conserved between influenza A and B. In a cultured cell system, marchantin E was further found to inhibit the growth of both H3N2 and H1N1 influenza A viruses, and marchantin A, E and perrotein F showed inhibitory properties towards the growth of influenza B. These marchantins also decreased the viral infectivity titer, with marchantin E showing the strongest activity in this assay. We additionally identified a chemical group that is conserved among different anti-influenza chemicals including marchantins, green tea catechins and dihydroxy phenethylphenylphthalimides. Our present results indicate that marchantins are candidate anti-influenza drugs and demonstrate the utility of the PA endonuclease assay in the screening of phytochemicals for anti-influenza characteristics.
Highlights
An influenza A pandemic in 1918, known as the Spanish flu, caused 50 million deaths worldwide [1,2,3]
Inhibition of influenza A and B viruses by marchantins Following in vitro selection using the endonuclease-inhibition assay, as a second screening, we examined the anti-viral activity of marchantin A (MA), ME, perrottetin F and plagiochin A against the influenza strains A/Hiroshima/52/2006 (H3N2), A/Solomon/3/ 2006 (H1N1) and B/Malaysia/2506/2004
We speculated that a combination of marchantin and oseltamivir would be effective against influenza, because it can inhibit two independent steps that are essential for the growth of this virus
Summary
An influenza A pandemic in 1918, known as the Spanish flu, caused 50 million deaths worldwide [1,2,3]. The avian H5N1 influenza A virus, which is highly pathogenic to humans, caused epidemics in Southeast Asia [4] and a new strain (Pandemic (H1N1) 2009) that emerged from pigs into humans caused a further pandemic in 2009 [5,6]. Strategies are needed to prevent future expansions of these viruses which remain a serious global health issue. Neuraminidase inhibitors such as oseltamivir are widely used as anti-influenza drugs [7,8], some side effects of these agents and the emergence of viral strains that are resistant to these agents have been reported [9,10,11]. The influenza A genome consists of segmented single stranded RNA (-) and its transcription and replication require the activity of a highly conserved RNA-dependent RNA polymerase [12,13,14]
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