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How does influenza virus a escape from amantadine?
Guangrong Qin1, Kunqian Yu, Ting Shi
1Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
The Journal of Physical Chemistry. B
|June 5, 2010
Summary
Amantadine (AMT) resistance in influenza A is linked to M2 protein mutations. This study reveals AMT binding within the M2 channel pore disrupts water flow, inhibiting viral function and clarifying drug resistance mechanisms.
Area of Science:
- Virology
- Structural Biology
- Computational Chemistry
Background:
- Antiviral drugs like amantadine (AMT) have shown reduced efficacy against influenza A virus.
- The M2 protein's transmembrane domain, particularly the S31N mutation, is implicated in AMT resistance.
Purpose of the Study:
- To elucidate the structural and mechanistic basis of amantadine resistance in influenza A virus M2 protein.
- To investigate the role of M2 protein structure and amantadine binding in channel function.
Main Methods:
- Utilized molecular dynamics (MD) simulations to model wild-type and S31N mutant M2 proteins.
- Employed quantum mechanics/molecular mechanics (QM/MM) calculations to analyze amantadine binding modes and interactions.
- Investigated the formation and modulation of water wires within the M2 channel.
Main Results:
- MD simulations showed amantadine binding at various positions within the M2 channel pore.
- QM/MM calculations confirmed these binding modes and their impact on channel function.
- Disruption of a critical water wire by amantadine binding was identified as essential for M2 channel inhibition.
- The S31N mutation prevents effective channel blocking, leading to amantadine resistance.
Conclusions:
- Amantadine binds within the pore of the M2 channel, supporting specific binding site hypotheses.
- The mechanism of amantadine resistance involves the failure to block the essential water wire in the S31N mutant.
- Findings provide insights into influenza A virus drug resistance and can aid in developing new antiviral therapies.
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