UB research group describes mechanism of action for drug to inhibit influenza A virus
<p>Researchers hope to design new multi-target antiviral drugs</p>
Researchers from the Faculty of Pharmacy and Food Sciences and the Institute of Biomedicine of the University of Barcelona (IBUB) led by professors F. Javier Luque and Santiago Vázquez have described the mechanism of action that explains why the antiviral drug amantadine curbs the infection and replication process of the influenza A virus.
The study, published in the Journal of the American Chemical Society, shows how amantadine binds with the virus's M2 channel and blocks it. During infection, the M2 protein on the viral envelope acts as a proton channel to pull proteins into the virus, which replicate the viral genome inside the infected cell.
As Professor F. Javier Luque explained, when amantadine binds with the M2 channel, it stops it from doing its job of transporting protons. Plus, the study also described for the first time that counterions play a key role in stabilizing the kind of amantadine bonding inside the M2 channel: bringing added electrostatic stabilization to boost the drug's inhibiting activity.
New explanation for different pharmacological responses to influenza A
This process of interaction with the drug is especially sensitive in the V27A mutation. According to the results, amantadine interacts differently in the presence of the V27A mutation, losing its inhibiting capacity. This is the only case in which a flu medicine is less effective in treating mutated influenza A viruses with resistance.
In previous studies, the UB team pharmacologically assessed compounds to block the mutant V27A channel, but with varying rates of success. The mechanism of action described in this new study explains the variation in pharmacological responses and opens the door to design new antiviral drugs for the resistant strain.
This line of work, being conducted by the team led by Professor Santiago Vázquez of the Department of Pharmacology, Toxicology and Therapeutic Chemistry, is exploring compounds with a greater hydrophobic surface than those used in the wild strain.
The team of scientists at the UB also hopes to study the bonding mechanisms of amantadine to the mutant S31N channel, prevalent in current strains of the influenza virus, and design multi-target compounds.
Related publication:
- Mechanism of the Pseudoirreversible Binding of Amantadine to the M2 Proton Channel. J. Am. Chem. Soc., 138 (47), 15345–15358 (November 7, 2016) DOI: 10.1021/jacs.6b07096