Hepatitis C virus non-structural protein 3-4A serine protease (NS3-4A)

The Hepatitis C virus (HCV) NS3-4A serine protease is a vital enzyme complex required for the replication and maturation of the virus [1, 11]. It is a non-covalent heterodimer consisting of the N-terminal domain of the non-structural protein 3 (NS3), which contains the catalytic triad (Ser139, His57, Asp81), and the NS4A protein, which serves as an essential cofactor for enzymatic activity and membrane anchoring [1, 5, 13]. The primary biological function of this protease is to cleave the viral polyprotein at four specific junctions—NS3/4A, NS4A/4B, NS4B/5A, and NS5A/5B—to release functional non-structural proteins necessary for the viral replication complex [1, 2, 11]. Beyond its role in viral processing, the NS3-4A protease also cleaves host cell signaling adapter proteins, such as MAVS and TRIF, thereby disrupting the host's innate immune response and facilitating persistent infection [2, 3, 13]. Because of its essential nature, the NS3-4A protease is a major target for direct-acting antiviral (DAA) drugs, including inhibitors like simeprevir, grazoprevir, and glecaprevir [6, 7, 8]. These inhibitors bind to the protease's active site, blocking polyprotein processing and potentially restoring the host's ability to mount an antiviral response [2, 3]. However, the high genetic variability of HCV leads to the rapid emergence of resistance-associated substitutions (RASs), such as mutations at positions R155, A156, and D168, which can significantly reduce drug efficacy and necessitate the use of combination therapies [7, 9, 12].

Other names

NS3 proteaseNS3/4A proteaseNS3-NS4A complexp-70HCV NS3-4A serine protease

Inhibition of the NS3-4A serine protease, preventing viral polyprotein cleavage and replication, and restoring host innate immune signaling.