Hepatitis C virus non-structural protein NS4A (NS4A)

Hepatitis C virus non-structural protein NS4A (NS4A) is a small, 54-amino-acid polypeptide that serves as an essential cofactor for the NS3 serine protease [1.1.1, 1.3.1]. Together, they form the NS3-NS4A complex, which is responsible for the proteolytic processing of the HCV polyprotein into functional units required for viral replication [1.1.2, 1.3.3]. Beyond its role in proteolysis, NS4A anchors the NS3-NS4A complex to the endoplasmic reticulum (ER) and mitochondrial membranes, enhances NS3 helicase activity, and regulates NS5A phosphorylation [1.2.1, 1.3.2]. The NS3-NS4A complex also plays a critical role in immune evasion by cleaving host proteins like MAVS and TRIF, thereby disrupting interferon signaling [1.3.3]. Due to its central role in the viral life cycle, the NS3-NS4A complex is a primary target for Direct-Acting Antivirals (DAAs), specifically NS3/4A protease inhibitors such as glecaprevir and voxilaprevir [1.3.3, 1.3.4]. These drugs bind to the protease active site or the NS3-NS4A interface, effectively halting viral replication and leading to high rates of sustained virologic response in patients with chronic hepatitis C [1.1.1, 1.3.4].

Other names

NS4Ap8Non-structural protein 4ANS3-NS4A cofactorHCV NS4A

Inhibition of the NS3-NS4A serine protease complex, preventing the cleavage of the viral polyprotein into functional non-structural proteins, thereby halting viral replication.