Antiviral agents for amantadine-resistant influenza A

The resistance to antiviral drugs is the main need for such a technology. Protons entry into the virus via the M2 channel is crucial for fusion of the membranes of the virus and endosome upon viral entry into the host cell. Thus, blocking of the M2 channel inhibits the virus. Indeed, adamantane derivatives, such as Amantadine and Rimantadine are approved anti-flu drugs. 
However, the virus has developed mutants that are resistant to these drugs. In particular, the S31N resistant mutant which dominates the viral population, making these drugs virtually obsolete. 
This technology offers a spectrum of antiviral drugs targeting the mutated Influenza M2 channel protein. Four novel compounds resulted from a virtual screening in search for new putative small molecule blockers of the channel. These compounds were shown to be effective in virus replication assays using the PR8 influenza A H1N1 virus, which contains the S31N mutation in the M2 channel that conveys resistance to amantadine.  
Further studies into these four compounds revealed several Structure-Activity Relationship (SAR) analogues with improved activity. Of these , 2 novel derivatives, synthesized based on the 4 compounds and active analogues, showed even better inhibitor activity.  

A new influenza treatment that blocks the M2 channel, thus inhibiting the virus activity, also in strains that are resistient to Amantadine (the former gold standard treatment).
We conducted virtual screening in search for new putative small molecule blockers of the channel, and came out with 74 compounds. We used Glide, a library of about 30,000 small molecules, and the M2 structures of wildtype virus which were known at the time. We also built homology model of the S31N mutant and docked our 74 promising hits to this structure; Of these, a selection of 14 compounds were tested in virus replication assays, and after further SAR modeling  of the top 4 performers, 2 novel analogues were chosen based on their high proformance.  

  • In-vitro Patch clamp assays 
  • In vivo influenza model (mouse experiments should start soon)  
  • Safety studies  

A provisional patent based on these preliminary results has been filed.

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