Hepatitis C virus (HCV) is a causative agent of hepatitis C infectious
disease that primarily affects the liver, ranging in severity from a mild illness
lasting a few weeks to a lifelong illness. The 9.6 kb RNA genome of HCV
encodes approximately 3000 amino acid polyprotein that must be processed by
host and viral proteases into both structural (S) and non-structural (NS) proteins,
respectively. Targeting the serine protease NS3 with an activating factor NS4A,
i.e., NS3/4A has been considered as one of the most attractive targets for the
development of anti-HCV therapy. Although there is no vaccine available, antiviral
medicines cure approximately 90% of the persons with hepatitis C infection.
On the other hand, efficacy of these medications can be hampered due to the rapid
drug and cross resistances. To date, all developed HCV NS3/4A inhibitors are
mainly peptide-based compounds derived from the cleavage products of substrate.
Specifically macrocyclic peptidomimetics have rapidly emerged as a classical
NS3/4A protease inhibitors for treating the HCV infection. This review highlights
the development of macrocyclic anti-HCV NS3/4A protease, as well as clinically
important inhibitors developed from linear peptides, discovered during the last 12
years (2003-2015) from all sources, including laboratory synthetic methods,
virtual screening and structure-based molecular docking studies. We emphasize
the rationale behind the design, study of structure-activity relationships, and
mechanism of inhibitions and cellular effect of the macrocyclic inhibitors.