Narlaprevir is a highly selective and orally active inhibitor of the hepatitis C virus non-structural protein 3 (HCV NS3), with a Ki value of 6nM and an EC90 value of 40nM[1]. HCV NS3 plays a critical role in viral replication and possesses both protease and helicase functions[2]. Narlaprevir inhibits viral replication in host cells by forming a reversible covalent bond with the active site of the HCV NS3 protease, and is commonly used in the treatment and research of chronic HCV infection[3,4,5].
In vitro, treatment of HCV genotype 1b subgenomic replicon Huh-7 cells with Narlaprevir (EC50 = 20nM, EC90 = 40nM) for 72h significantly inhibited HCV RNA replication[6].
In vivo, Narlaprevir (10mg/kg) was administered orally to rats, with a bioavailability of 46% and a liver concentration of 750ng/g 8h after administration[1].
References:
[1] ARASAPPAN A, BENNETT F, BOGEN S L, et al. Discovery of narlaprevir (SCH 900518): a potent, second generation HCV NS3 serine protease inhibitor[J]. ACS Medicinal Chemistry Letters, 2010, 1(2): 64-69.
[2] ZHOU T, REN X, ADAMS R L, et al. NS3 from hepatitis C virus strain JFH-1 is an unusually robust helicase that is primed to bind and unwind viral RNA[J]. Journal of Virology, 2018, 92(1): e01253-17.
[3] BAI Y, YE F, FENG Y, et al. Structural basis for the inhibition of the SARS-CoV-2 main protease by the anti-HCV drug narlaprevir[J]. Signal Transduction and Targeted Therapy, 2021, 6(1): 51.
[4] ISAKOV V, KOLODA D, TIKHONOVA N, et al. Pharmacokinetics of the new hepatitis C virus NS3 protease inhibitor narlaprevir following single-dose use with or without ritonavir in patients with liver cirrhosis[J]. Antimicrobial Agents and Chemotherapy, 2016, 60(12): 7098-7104.
[5] MARTINO S D, PETRI G L, DE ROSA M. Hepatitis C: the story of a long journey through first, second, and third generation NS3/4A peptidomimetic inhibitors. What did we learn?[J]. Journal of Medicinal Chemistry, 2024, 67(2): 885-921.
[6] TONG X, ARASAPPAN A, BENNETT F, et al. Preclinical characterization of the antiviral activity of SCH 900518 (narlaprevir), a novel mechanism-based inhibitor of hepatitis C virus NS3 protease[J]. Antimicrobial Agents and Chemotherapy, 2010, 54(6): 2365-2370.
Narlaprevir是一种具有高效选择性和口服活性的丙型肝炎病毒的非结构蛋白3（HCV NS3）抑制剂，Ki值为6nM，EC90值为40nM[1]。HCV NS3在病毒复制中起关键作用，具有蛋白酶和解螺旋双重功能[2]。Narlaprevir通过与HCV的NS3蛋白酶活性位点进行可逆共价结合，抑制病毒在宿主细胞内的复制，通常用于慢性HCV的治疗和研究[3,4,5]。
在体外，Narlaprevir（EC50 = 20nM, EC90 = 40nM）处理HCV基因1b型亚基因组复制子Huh-7细胞72h，显著抑制了HCV RNA复制[6]。
在体内，Narlaprevir（10mg/kg）通过口服给药于大鼠，生物利用度为46%，给药后8h肝脏内浓度为750ng/g[1]。