Anti-Influenza Activity of C60 Fullerene Derivatives

Masaki Shoji,Shigeo Nakamura,Yuma Iwai,Riku Shirayama,Dai Hatakeyama,Tadahiko Mashino,Takeshi Okutani,Etsuhisa Takahashi,Hiroshi Kido,Takashi Kuzuhara,Yuka Morita,Noriko Echigo,Paul Digard

doi:10.1371/journal.pone.0066337

Abstract

The H1N1 influenza A virus, which originated in swine, caused a global pandemic in 2009, and the highly pathogenic H5N1 avian influenza virus has also caused epidemics in Southeast Asia in recent years. Thus, the threat from influenza A remains a serious global health issue, and novel drugs that target these viruses are highly desirable. Influenza A RNA polymerase consists of the PA, PB1, and PB2 subunits, and the N-terminal domain of the PA subunit demonstrates endonuclease activity. Fullerene (C60) is a unique carbon molecule that forms a sphere. To identify potential new anti-influenza compounds, we screened 12 fullerene derivatives using an in vitro PA endonuclease inhibition assay. We identified 8 fullerene derivatives that inhibited the endonuclease activity of the PA N-terminal domain or full-length PA protein in vitro. We also performed in silico docking simulation analysis of the C60 fullerene and PA endonuclease, which suggested that fullerenes can bind to the active pocket of PA endonuclease. In a cell culture system, we found that several fullerene derivatives inhibit influenza A viral infection and the expression of influenza A nucleoprotein and nonstructural protein 1. These results indicate that fullerene derivatives are possible candidates for the development of novel anti-influenza drugs.

Highlights

In 1918, an influenza A pandemic caused 50 million deaths worldwide [1], and the development of strategies that can be used to prevent future expansions of this virus continues to be an important endeavor [2]
We speculate that PA endonuclease would contain very effective targets for the development of novel anti-influenza A drugs, as we have shown that several chemicals, e.g., catechins, phenethylphenyl phthalimide analogs, and marchantin analogs, inhibit this endonuclease and possess antiviral activity [15,16,17]
We found that the fullerene derivatives inhibit influenza PA endonuclease activity and viral infection

Summary

Introduction

In 1918, an influenza A pandemic caused 50 million deaths worldwide [1], and the development of strategies that can be used to prevent future expansions of this virus continues to be an important endeavor [2]. The influenza A genome consists of segmented single-stranded RNA (-), and its transcription and replication require the activity of a highly conserved RNAdependent RNA polymerase [10,11]. This polymerase is essential for the propagation of the influenza A virus and is a very promising target for the development of antiviral drugs. We speculate that PA endonuclease would contain very effective targets for the development of novel anti-influenza A drugs, as we have shown that several chemicals, e.g., catechins, phenethylphenyl phthalimide analogs, and marchantin analogs, inhibit this endonuclease and possess antiviral activity [15,16,17]

Methods

Results

Conclusion