Description:

Structure, mechanism and pharmacological inhibition of membrane proteins from influenza A virus M2 proton channel to integrins

The M2 proton channel from influenza A virus is an essential component of the viral envelope, and this protein is required for acidification of the inside of the virus once engulfed by the endosome. M2 is also the target of the anti-influenza drugs amantadine and rimantadine, although drug-resistance has become a major problem in the last decade. To investigate the mechanism by which protons are transported along water wires through the channel we have determined very high resolution crystal structures at room temperature and using X-ray free electron laser crystallography. The structures provide insight into the mechanism by which protons diffuse through clusters of water molecules to histidine residues deep within the pore. We next used this structural insight to design new drugs that inhibit the most problematic drug-resistant mutant forms of the channel.

Next I will discuss the design of inhibitors of the integrin v1 that block local activation of TGF-, and the use of these drugs for the treatment of fibrotic disorders. Finally, I will discuss a new role for integrin-mediated interactions between airway smooth muscle cells and the extracellular matrix in severe asthma, and the development of inhibitors that block this process.