| text | Hepatitis C virus (HCV) encodes a polyprotein, which is proteolytically processed to produce four structural proteins (C, E1, E2, and p7) and six nonstructural (ns) proteins (ns2, ns3, ns4A, ns4B, ns5A and ns5B) (Hijikata M et al. 1991; Grakoui A et al. 1993). The viral ns3 harbors serine protease activity at the N-terminal and a nucleoside-triphosphatase- (NTPase-) dependent RNA helicase activity (NTPase/RNA helicase) at the C-terminal (Penin F et al. 2004). Both enzyme activities are essential for viral replication. HCV ns3 forms a complex with a cofactor ns4A, which targets ns3 to the membrane localization and is required for the most efficient enzymatic activity of ns3 (Lin C & Rice CM 1995; Kwong AD et al. 1999; Shiryaev SA et al. 2012). The protease activity of ns3:ns4A cleaves the HCV polyprotein releasing individual viral proteins (Grakoui A et al. 1993; Kolykhalov AA et al. 1994). It also inhibits host-mediated antiviral responses by cleaving host proteins, including TIR domain containing adaptor inducing IFN-β (TRIF) and mitochondrial antiviral signaling protein (MAVS) (Meylan E et al. 2005; Morikawa K et al. 2011; Bender S et al. 2015). There is a wide variety of synthetic peptidomimetic inhibitors of HCV ns3:ns4A protease activity that directly bind to the ns3:ns4A complex and may therefore block viral replication by inhibiting viral polyprotein processing and restore host IFN-signaling pathways (reviewed in Salam KA & Akimitsu N 2013). The ns3:ns4A protease inhibitors can be classified into two groups. The inhibitors of the first group (such as boceprevir and telaprevir) are linear α-ketoamides that form a covalent bond with the active site of the enzyme in a reversible way (Perni RB et al. 2006; Pan Q et al. 2012; reviewed in Salam KA & Akimitsu N 2013). The second group of noncovalent reversible inhibitors can be further sub-classified based on their structure: linear (asunaprevir) (Scola PM et al. 2014), P1-P3 macrocyclic (simeprevir and paritaprevir) (Izquierdo L 2014), and P2-P4 macrocyclic compounds (grazoprevir) (Neelamkavil SF et al. 2015; Velázquez F et al. 2016), where 'P' refers to a substrate amino acid residue in the peptidomimetic inhibitors that interacts with the corresponding binding site (S1-S4) within the binding pocket of the ns3:ns4A protease. The rapid mutation rate of HCV may lead to an emergence of drug-resistant viral strains and in some cases treatment failure (Cento V et al. 2012; Gottwein JM et al. 2011; reviewed in Martinez MA & Franco S 2021). Structural studies revealed molecular mechanisms behind the activity of ns3:ns4A protease inhibitors and mechanisms by which drug resistance occurs (Soumana DI et al. 2014; Özen A et al. 2019; Timm J et al. 2020; Matthew AN et al. 2020). These data may aid to drug design strategies to avoid resistance (Soumana DI et al. 2014, 2016; Özen A et al. 2019; Timm J et al. 2020; Matthew AN et al. 2020). This Reactome event shows interaction of the HCV subtype 1a ns3:ns4A protease with FDA approved drugs such as boceprevir, asunaprevir, simeprevir, paritaprevir, glecaprevir, telaprevir and grazoprevir. Some other drugs are approved elsewhere only; vaniprevir was approved in Japan in 2014, and narlaprevir in Russia in 2016. |
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