The Most Conservative Protein of Flu Virus: Death Sentence or Life Saver?
5 Sep, 2007 01:30 pm
If there were ?popularity awards? for viral proteins, the two most likely candidates would be two proteins exposed on the surface of influenza (flu) virus, hemaglutinin and neuraminidase. Just a few years ago, these two proteins were known only to the biomedical community. Since then, they have made their journey from the Journal of Virology to the front pages of the New York Times and Wall Street Journal. However, there is a third protein on the surface of flu virus, mysterious M2.
Contrary to hemaglutinin and neuraminidase, which constantly change, M2 is extremely conserved and does not change much between human and avian strains of the virus. A lot is known about M2, even more remains to be understood. Here is a conundrum: the number of M2 molecules on the viral surface is 40 to 100 times less than the number of HA molecules.
However, on the surface of a virus infected cell, these two proteins are present in comparable numbers. What is the biological meaning of this? Does it help the virus or the cell?
Scientists at Cure Lab, Inc., a biotechnology company based in
Each human and avian cell is covered with a membrane that is impermeable to ions. In order for the ions to get in and out of the cells they have to go through specific molecular gates, which are tightly regulated by cellular “gate keepers”. M2 protein forms pores in cell membranes permeable for positively charged ions. Dr Shneider and his group at Cure Lab, Inc. have demonstrated that this “ion smuggling” by viral M2 proteins may be the molecular mechanism of cell killing. But if killing the host cells by M2 protein is a part of the viral strategy, then 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.
This hypothesis has to be validated. Will the drug blocking ion channeling through M2 pore really prevent M2-induced cell killing? The typical approach to answer a question like this is to change the protein by introducing a mutation into the gene coding for this protein, which would have the effect of a future drug. For example, if a future drug blocks ion transport through M2, then the model mutations should block the ion conductivity of M2. If the mutated M2 protein, which is incapable of ion transferring across the cell membrane will continue to kill the cells as efficiently as the wild type form, then creating a drug blocking M2 as an ion channel will be of no avail. Contrary, if the mutants incapable of efficient ion channeling are less toxic for the cells, then the drug reducing ion channeling would prevent cell death by M2.
In collaboration with Dr. Vladimir L. Gabai from Boston University, and Dr. Shamil R. Sunyaev from Harvard Medical School, scientist from Cure Lab, Inc. have developed mutant forms of M2 protein, where the ion channel is “blocked”. They have shown that these specific mutations introduced into the protein significantly reduces its ability to kill the cell.
Interestingly, two out of three currently available anti-flu drugs, amantadine and rimantadine, also act through M2 protein. It is unlikely, that any new antiviral drugs could be discovered in the future without rational drug design coming from understanding and validating a molecular target. Dr. Shneider said that “an M2-targeted search for new anti-influenza drugs could lead to a new generation of medicines which will complement those currently used for influenza disease prevention and treatment.” Dr Petr Ilyinskii, a principal scientist at Cure Lab, and the first author on the paper also pointed out that this is especially important since an increasing number of influenza strains are becoming resistant to the drugs that are now widely used.”
Ilyinskii O. P., et al, Toxicity of Influenza A Virus Matrix Protein 2 for Mammalian Cells is Associated with its Intrinsic Proton-Channeling Activity, Cell Cycle, 15 August 2007