The 9.6 kb plus-strand RNA genome of HCV encodes a long polyprotein precursor
of ~3,000 amino acids, which is processed by cellular and viral proteases to 10
individual proteins. One of the HCV proteases, NS3-4A serine protease, is a noncovalent
heterodimer consisting of a catalytic subunit (the N-terminal one-third
of NS3 protein) and an activating cofactor (NS4A protein), and is responsible for
cleavage at four sites of the HCV polyprotein. HCV NS3-4A protease is essential
for viral replication in cell culture and in chimpanzees, and has been considered as
one of the most attractive targets for developing novel anti-HCV therapies. However,
discovery of small-molecule, selective inhibitors against HCV NS3-4A protease as
oral drug candidates has been hampered by its shallow substrate-binding groove and
the lack of robust, reproducible viral replication models in cell culture or in small
animals. Nevertheless, decade-long intense efforts by many groups have largely
overcome these two obstacles and provided fruitful understanding of its biological
functions, biochemistry, and three-dimensional structures, culminating in recent
demonstration of proof-of-concept anti-HCV activities in patients. This chapter
will review key findings in these areas, and focus on the discovery and clinical
development of HCV NS3-4A protease inhibitors as novel antiviral therapies.
[hepatitis - buku HCV: chapter 6] |