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.

Fullerenes (represented by buckminsterfullerene, C60) are a new kind of organic compound with a cage-like structure. A great deal of attention has been focused on their unique properties. From the viewpoint of drug discovery, fullerenes could be novel lead compounds for drug discovery. However, fullerenes are poorly soluble in aqueous media. Incorporation of water-soluble groups into the fullerene core enables investigation of its biological activities. Certain fullerene derivatives show inhibitory activity against human immunodeficiency virus reverse transcriptase. Hepatitis C virus RNA polymerase is also inhibited by fullerene derivatives. Therefore, fullerene derivatives are candidate antiviral agents. In addition, fullerene derivatives exhibit antiproliferative activity by inducing apoptosis related to the generation of reactive oxygen species. Fullerene derivatives also have the potential to be anticancer drugs.