NarlaprevirはC型肝炎ウイルス非構造タンパク質3（HCV NS3）の高選択的で経口活性の阻害剤であり、Ki値は6nMで、EC90値は40nMである[1]。HCV NS3はウイルスの複製で肝心な役割を果たし、プロテアーゼとヘリカーゼ機能の両方を持っている[2]。Narlaprevirは、HCV NS3プロテアーゼの活性部位と可逆的な共有結合を形成することで、宿主細胞でウイルスの複製を阻害し、慢性HCV感染症の治療と研究に一般的に使われる[3,4,5]。
In vitro（体外）実験で、HCV遺伝子型1bサブゲノムレプリコンHuh-7細胞をNarlaprevir（EC50 = 20nM、EC90 = 40nM）で72時間処理したところ、HCV RNAの複製を著しく阻害した[6]。
In vivo（体内）実験で、Narlaprevir（10mg/kg）をラットに経口投与し、投与の8時間後、生物利用度は46%で、肝臓濃度は750ng/gであった[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.