Plugging the holes in hepatitis C virus antiviral therapy
A growing number of RNA viruses are known to depend on virus-encoded ion channels for efficient production of infectious virions and, in some cases, for the subsequent infection of cells. Viroporins are small hydrophobic proteins, usually less than 100 amino acids in length, and typically contain one or two transmembrane domains; 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. 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 (Plugging the holes in hepatitis C virus antiviral therapy. PNAS USA 28 July 2009).
In a recent issue of PNAS, researchers describe the structure of a complete viroporin complex, the p7 ion channel of hepatitis C virus (HCV), at 16-Å resolution by using single-particle electron microscopy (The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy. 2009 PNAS USA 106: 12712–12716). The hexameric p7 complex (42 kDa) is one of the smallest objects to be visualized by these methods to date which, combined with the hydrophobic nature of p7, makes this work an impressive technical achievement. The study provides optimism that p7 inhibitors could one day become part of HCV therapy.
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