Plugging the holes in hepatitis C virus antiviral therapy

A growing number of RNA viruses are now known to depend on virus-encoded ion channels for efficient production of infectious virions and, in some cases, for the subsequent infection of naive cells. So-called viroporins are small hydrophobic proteins, usually less than 100 aa in length, and typically contain 1 or 2 transmembrane domains (TMDs); oligomerization is therefore necessary for the formation of ion channel complexes. By far the best-characterized viroporin is the M2 proton channel of influenza A virus, which is the target for the antiviral drugs amantadine and rimantadine (1). M2 sets a precedent for viroporins as therapeutic targets that has driven research into the ion channels of other clinically important viruses. In the light of rapid RNA virus evolution generating drug resistance, new compounds targeting viroporins could be a valuable addition to future combinatorial antiviral strategies. Difficulties associated with working with membrane proteins in high-throughput systems lend support to a rational approach for drug development based on the availability of high-resolution molecular structures.