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Mechanism of Influenza Drug Resistance

Curator: Larry H Bernstein, MD, FCAP

 

Very interesting read.

 

 

Long Time Scale GPU Dynamics Reveal the Mechanism of Influenza Drug Resistance

 

 

Multidrug resistance of the pandemic H1N1-2009 strain of influenza has been reported due to widespread treatment using the neuraminidase (NA) inhibitors, oseltamivir (Tamiflu), and zanamivir (Relenza). From clinical data, the single I223R (IR(1)) mutant of H1N1-2009 NA reduced efficacy of oseltamivir and zanamivir by 45 and 10 times, respectively. More seriously, the efficacy of these two inhibitors against the double mutant I223R/H275Y (IRHY(2)) was significantly reduced by a factor of 12 374 and 21 times, respectively, compared to the wild-type.

 

This has led to the question of why the efficacy of the NA inhibitors is reduced by the occurrence of these mutations and, specifically, why the efficacy of oseltamivir against the double mutant IRHY was significantly reduced, to the point where oseltamivir has become an ineffective treatment.

 

In this study, 1 μs of molecular dynamics (MD) simulations was performed to answer these questions. The simulations, run using graphical processors (GPUs), were used to investigate the effect of conformational change upon binding of the NA inhibitors oseltamivir and zanamivir in the wild-type and the IR and IRHY mutant strains.

 

These long time scale dynamics simulations demonstrated that the mechanism of resistance of IRHY to oseltamivir was due to the loss of key hydrogen bonds between the inhibitor and residues in the 150-loop. This allowed NA to transition from a closed to an open conformation.

 

Oseltamivir binds weakly with the open conformation of NA due to poor electrostatic interactions between the inhibitor and the active site. The results suggest that the efficacy of oseltamivir is reduced significantly because of conformational changes that lead to the open form of the 150-loop.

 

This suggests that drug resistance could be overcome by increasing hydrogen bond interactions between NA inhibitors and residues in the 150-loop, with the aim of maintaining the closed conformation, or by designing inhibitors that can form a hydrogen bond to the mutant R223 residue, thereby preventing competition between R223 and R152.

 

Christopher J. Woods, Maturos Malaisree, Naruwan Pattarapongdilok, Pornthep Sompornpisut, Supot Hannongbua and Adrian J. Mulholland. Long Time Scale GPU Dynamics Reveal the Mechanism of Drug Resistance of the Dual Mutant I223R/H275Y Neuraminidase from H1N1-2009 Influenza Virus. Biochemistry, 51 (21), pp 4364–4375, 2012. [doi: 10.1021/bi300561n]

 

Oseltamivir

Oseltamivir (Photo credit: Wikipedia)

 

 

 

 

 

 

 

 

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CategoryArticlesLife Science

 

 

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