Discovery and development of NS5A inhibitors

Nonstructural protein 5A (NS5A) inhibitors belong to a class of antiviral drugs called protease inhibitors. They are direct acting antiviral agents (DAAs) that target viral proteins, and their development was a culmination of increased understanding of the viral life cycle. However, their mechanism of action is complex and not fully understood. NS5A inhibitors were the focus of much attention when they emerged as a part of the first curative treatment for hepatitis C virus (HCV) infections in 2014. Favorable characteristics have been introduced through varied structural changes, and structural similarities between NS5A inhibitors that are clinically approved are readily apparent. Despite the recent introduction of numerous new antiviral drugs, resistance is still a concern and these inhibitors are therefore always used in combination with other drugs.

HCV is a positive-sense single-stranded RNA virus that has been demonstrated to replicate in the of both humans and chimpanzees. A single HCV polyprotein is translated, and then cleaved by cellular and viral proteases into three structural proteins (core, E1, and E2) and seven nonstructural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B).

HCV is among the leading causes of liver disease around the world. It is transmitted by blood and is most commonly contracted through the use of infected needles. Patients suffering from chronic HCV infection are at significant risk of cirrhosis and , which are the leading causes of death for those infected.

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