New Generation of Anti-flu Drugs Suppress Ion Channel Formation

Researchers have found that the influenza virus M2 protein kills mammalian cells through the formation of proton channels in the plasma membrane of the infected cells.

Molecules of influenza matrix protein 2 (M2) are organized in tetramers that are highly conserved between avian and human strains of the virus. Investigators at Cure Lab, Inc. (Canton, MA, USA) tested the potential value of drugs that would inactivate M2 activity. To this end they constructed an M2 point-mutant (M2pm) protein that contained amino acid changes designed to block proton channel formation via introduction of large hydrophobic residues. Cell cultures were exposed to either M2pm or the normal (wild type) protein, M2wt.

Results published in the August 15, 2007, issue of Cell Cycle revealed that the mutant protein was significantly less toxic upon transient transfection in vitro than was M2wt. M2wt rapidly decreased mitochondria membrane potential reflecting the transmembrane proton gradient, while M2pm was markedly less efficient.

"This effect may constitute a previously unknown mechanism of influenza virus pathogenicity,” said senior author Dr. Alex Shneider, CEO of CureLab, Inc. "If so, drugs that are shown to prevent M2-dependent cell killing have the potential to be used for the treatment of flu. Developing drugs which block M2 ion channels could reduce or eliminate M2-induced cell death, and thus may be a new strategy for targeted development of anti-influenza drugs.”


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