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Mechanism of Action of Membrane Proteins

Tech ID:
Principal Investigator:
Timothy Cross
Licensing Manager:

The present invention relates to the atomistic functional understanding of the M2 protein from the influenza A virus. This acid-activated selective proton channel has been the subject of numerous conductance, structural, and computational studies. Previously, little was known at the atomic level about the heart of the functional mechanism of this tetrameric protein, a tetrad of HxxxW residues. The structure of the M2 conductance domain in a lipid bilayer is disclosed and displays the defining features of the native protein that have not been attainable from structures solubilized by detergents. A detailed mechanism for acid activation and proton conductance is provided and elucidates many observations on the M2 proton conductance. The present invention provides a method based on the comparative study of solid-state NMR spectra in which detecting a change in resonance will determine that a drug candidate has bound to a histidine tetrad of a viral protein.

Influenza A and B viruses cause a highly contagious respiratory disease in humans resulting in approximately 36,000 deaths in the United States annually. The only other drugs for inhibiting the M2 protein from Influenza A virus are no longer effective due to viral mutations. The knowledge of unique geometry associated with the tetramer of this protein may permit the development of drugs to inhibit this proven target. Unlike previous drugs that served to plug the pore formed by this protein across the viral membrane, drugs that targeted the channels unique chemistry could be much more specific for this target. The immediate application is to computationally model drugs that would bind with this chemistry and then conduct drug screening efforts to optimize drug binding affinity. Targeting the novel chemistry associated with function of this protein provides a new opportunity for drug development against the deadly Influenza A virus.