Hepatitis C virus (HCV) is a human pathogen with high morbidity. The HCV NS3/4A protease is essential for viral replication and is one of the top three drug targets. BMS-986144 is a third-generation, pan-genotype NS3/4A protease inhibitor for the treatment of Hepatitis C Virus infection.

Chronic infection with HCV is a leading cause of end-stage liver disease and hepatocellular carcinoma. In particular, HCV is an RNA virus with a cytoplasmic life cycle. Therapies that prevent virus replication can ultimately eradicate the virus from the host. Besides, this Therapy also reduces both the risk of development of liver disease and the risk of cancer. The nonstructural proteins of HCV play important roles in viral production and replication.

Three viral proteins NS3/4A serine protease, NS5A IFN resistance protein, and NS4B polymerase are the major drug targets for the existing antiviral therapeutics. The NS3/4A protease is responsible for the selective cleavage of polyproteins into individual viral proteins (NS4A, NS4B, NS5A, and NS5B). Moreover, HCV NS3 is a multifunctional protein that composes of a protease domain and a helicase domain. Furthermore, The NS3/4A protease of HCV is an important antiviral target.

In particular, in vitro profiling of BMS-986144 for inhibitory activity toward a panel of enzymes and receptors reveals no significant off-target activity at 10 μM. However, the vitro cytotoxicity profile in Huh7 and MT2 cell lines is favorable (CC50=25 and 34 μM, respectively), providing for a significant therapeutic index in vitro. Especially, the discovery of BMS-986144 bases on a P1–P3 macrocyclic tripeptide motif.

All in all, BMS-986144 is a pan-genotypic hepatitis C virus NS3/4A protease inhibitor.

Li-Qiang Sun, et al. 2020 Dec 10;63(23):14740-14760.