Protease inhibitors
G. Rao, Vertex Pharmaceuticals
The NS3 protease of Hepatitis C virus has emerged as an attractive
target for drug design. An interesting aspect of this serine protease
is that it requires binding of a cofactor (NS4A) peptide to be fully
active. The first crystal structure of truncated NS3 protease - NS4A
peptide complex shows that the NS4A peptide intercalates within a
beta sheet of the enzyme core, forming an integral part of the tertiary
structure. A structure of the truncated NS3 protease without NS4A
shows not only a significant disorder of the structure with the
N-terminal 30 residues in an extended conformation, but also a
non-optimal orientation of the catalytic triad residues.