Abstract

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.