The hepatitis C virus (HCV) infection is a major and rising global health
problem, affecting more than 71 million people worldwide. HCV is connected with
several hepatic and extrahepatic disorders, containing several malignancies. Improved
HCV detection with combined simple, well-tolerated treatments could reduce the need
for liver transplantation and HCV related mortality. The latest therapeutic advances
might convert chronic HCV into a routinely treatable disease. The introduction of
direct-acting antivirals (DAAs) has improved efficacy and tolerance of treatments with
high cure rates. DAAs target specific nonstructural proteins of the HCV with
consequential interference with viral replication and consequently infection. The
majority of the FDA approved drugs for HCV and those pending approval are small
molecule drugs, especially those that utilize the viral inhibitor mechanisms of action
and favor the HCV nonstructural proteins as their targets. Therefore, DAAs represent
the most promising anti-HCV drugs that carry the least risk of drug failure during
clinical trials. NS3/4a protease inhibitors have become the basis for HCV treatment as
most new therapies contain an inhibitor from this class. It is reported that the approach
for combating chronic viral infections is best achieved by a combination of several
strategies, by means of inhibiting several targets. Moreover, the best promising strategy
for fighting HCV is most similar to the anti-HIV therapy. A literature review was
conducted to identify published clinical trial results regarding DAA combination
therapy with third generation NS3/4a protease inhibitors. Detailed attention is given to
the chemistry of the approved NS3/4a drugs and candidate therapeutics in the advanced
stages of development. In this regard, a review of key drug design and organic
synthesis stages is presented for anti-NS3/4A DAAs.
Keywords: Chemical Synthesis, Clinical Trials Data, Drug Design, Direct-Acting
Antivirals, Hepatitis C Virus, NS3/4A protease, Protease Inhibitors.
