The Influenza Matrix 2 (M2) protein is the target of Amantadine and Rimantadine which block its H+ channel activity. However, the potential of these aminoadamantyls to serve as anti-flu agents is marred by the rapid resistance that the virus develops against them. Herein, using a cell based assay that we developed, we identify two new aminoadamantyl derivatives that show increased activity against otherwise resistant M2 variants. In order to understand the distinguishing binding patterns of the different blockers, we computed the potential of mean force of the drug binding process. The results reveal that the new derivatives are less mobile and bind to a larger pocket in the channel. Finally, such analyses may prove useful in designing new, more effective M2 blockers as a means of curbing influenza. This article is part of a Special Issue entitled: Viral Membrane Proteins - Channels for Cellular Networking.
Bibliographical noteFunding Information:
This work was supported in part by grants from The Rudin Fellowship Trust , and grants from the Israeli Science Foundation ( 1581/08 ) and the German Israel Foundation . ITA is the Arthur Lejwa Professor of Structural Biochemistry at the Hebrew University of Jerusalem.
- Anti-flu agent
- Cell based assay
- Channel blocker
- Potential of mean force