From Acid Activation Mechanisms of Proton Conduction to Design of Inhibitors of the M2 Proton Channel of Influenza A Virus

With an estimated 1 billion people affected across the globe, influenza is one of the most serious health concerns worldwide. Therapeutic treatments have encompassed a number of key functional viral proteins, mainly focused on the M2 proton channel and neuraminidase. This review highlights the efforts spent in targeting the M2 proton channel, which mediates the proton transport toward the interior of the viral particle as a preliminary step leading to the release of the fusion peptide in hemagglutinin and the fusion of the viral and endosomal membranes. Besides the structural and mechanistic aspects of the M2 proton channel, attention is paid to the challenges posed by the development of efficient small molecule inhibitors and the evolution toward novel ligands and scaffolds motivated by the emergence of resistant strains.

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pH Titration and Acid Activation of the Full-Length Influenza a M2 Proton Channel in Lipid Bilayers

Biophysical Journal ◽

10.1016/j.bpj.2014.11.1365 ◽

2015 ◽

Vol 108 (2) ◽

pp. 246a

Author(s):

Yimin Miao ◽

Riqiang Fu ◽

Huan-Xiang Zhou ◽

Huajun Qin ◽

Timothy A. Cross

Keyword(s):

Lipid Bilayers ◽

Influenza A ◽

Full Length ◽

Proton Channel ◽

Acid Activation ◽

Ph Titration ◽

M2 Proton Channel

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Acid activation mechanism of the influenza A M2 proton channel

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1615471113 ◽

2016 ◽

Vol 113 (45) ◽

pp. E6955-E6964 ◽

Cited By ~ 36

Author(s):

Ruibin Liang ◽

Jessica M. J. Swanson ◽

Jesper J. Madsen ◽

Mei Hong ◽

William F. DeGrado ◽

...

Keyword(s):

Free Energy ◽

Proton Transport ◽

Influenza A ◽

Conduction Mechanism ◽

Transmembrane Domain ◽

Proton Conduction ◽

Proton Flux ◽

Activation Mechanism ◽

Proton Channel ◽

Acid Activation

The homotetrameric influenza A M2 channel (AM2) is an acid-activated proton channel responsible for the acidification of the influenza virus interior, an important step in the viral lifecycle. Four histidine residues (His37) in the center of the channel act as a pH sensor and proton selectivity filter. Despite intense study, the pH-dependent activation mechanism of the AM2 channel has to date not been completely understood at a molecular level. Herein we have used multiscale computer simulations to characterize (with explicit proton transport free energy profiles and their associated calculated conductances) the activation mechanism of AM2. All proton transfer steps involved in proton diffusion through the channel, including the protonation/deprotonation of His37, are explicitly considered using classical, quantum, and reactive molecular dynamics methods. The asymmetry of the proton transport free energy profile under high-pH conditions qualitatively explains the rectification behavior of AM2 (i.e., why the inward proton flux is allowed when the pH is low in viral exterior and high in viral interior, but outward proton flux is prohibited when the pH gradient is reversed). Also, in agreement with electrophysiological results, our simulations indicate that the C-terminal amphipathic helix does not significantly change the proton conduction mechanism in the AM2 transmembrane domain; the four transmembrane helices flanking the channel lumen alone seem to determine the proton conduction mechanism.

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