MK-5172 is a selective inhibitor of hepatitis C virus (HCV) NS3/4a protease, exhibiting broad-spectrum activity against multiple genotypes and drug-resistant variants, and capable of inhibiting SARS-CoV-2 3CL protease activity[1-2]. MK-5172 demonstrates favorable liver-targeting properties and sustained virological responses in studies, making MK-5172 applicable for research related to chronic hepatitis C and MK-5172 co-infection with HIV[3-4].
In vitro, pretreatment of Vero E6 cells or human-derived 293T-ACE2 cells with MK-5172 (0.55-20.5μM) for 2 hours, followed by infection with SARS-CoV-2 virus (MOI=0.025–2PFU/cell) for 48 hours, significantly inhibited viral replication[5]. Treatment of GT1a (H77) replicon cells with MK-5172 (0.4–35nM) for 72 hours, MK-5172 significantly suppressed HCV RNA replication (EC₉₀=0.9nM) and maintained inhibitory activity against NS5A-resistant variants[6].
In vivo, intraperitoneal injection of MK-5172 (10mg/kg/day) for 5 days (starting from day 5 after MC-38 colon adenocarcinoma cell transplantation) in PD-1-mCherry-SMASh homozygous knock-in (KI) mice significantly suppressed tumor growth[7]. Oral administration of MK-5172 (3mg/kg) once daily for 3 consecutive days in diabetic model C57BL/6 mice significantly restored glucose homeostasis[8].
References:
[1] Vallet-Pichard A, Pol S. Grazoprevir/elbasvir combination therapy for HCV infection. Therap Adv Gastroenterol. 2017 Jan;10(1):155-167.
[2] Al-Salama ZT, Deeks ED. Elbasvir/Grazoprevir: A Review in Chronic HCV Genotypes 1 and 4. Drugs. 2017 May;77(8):911-921.
[3] Karaoui LR, Mansour H, Chahine EB. Elbasvir-grazoprevir: A new direct-acting antiviral combination for hepatitis C. Am J Health Syst Pharm. 2017 Oct 1;74(19):1533-1540.
[4] Wang SJ, Huang CF, Yu ML. Elbasvir and grazoprevir for the treatment of hepatitis C. Expert Rev Anti Infect Ther. 2021 Sep;19(9):1071-1081.
[5] Bafna K, White K, Harish B, et al. Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture. Cell Rep. 2021 May 18;35(7):109133.
[6] Lahser FC, Bystol K, Curry S, et al. The Combination of Grazoprevir, a Hepatitis C Virus (HCV) NS3/4A Protease Inhibitor, and Elbasvir, an HCV NS5A Inhibitor, Demonstrates a High Genetic Barrier to Resistance in HCV Genotype 1a Replicons. Antimicrob Agents Chemother. 2016 Apr 22;60(5):2954-64.
[7] Naruse C, Sugihara K, Miyazaki T, et al. A degron system targeting endogenous PD-1 inhibits the growth of tumor cells in mice. NAR Cancer. 2022 Jun 17;4(2):zcac019.
[8] Shao J, Li S, Qiu X, et al. Engineered poly(A)-surrogates for translational regulation and therapeutic biocomputation in mammalian cells. Cell Res. 2024 Jan;34(1):31-46.
MK-5172是一种丙型肝炎病毒（HCV）NS3/4a蛋白酶选择性抑制剂，对多种基因型及耐药变异株均具有广谱活性，并能抑制SARS-CoV-2 3CL蛋白酶活性[1-2]。MK-5172在研究中显示出良好的肝脏靶向性和持久的病毒学应答，可用于慢性丙型肝炎及其与HIV共感染的相关研究[3-4]。
在体外，MK-5172（1.25–50μM）预处理Vero E6细胞或人源293T-ACE2细胞2小时，随后以SARS-CoV-2病毒（MOI=0.025–2PFU/cell）感染48小时，MK-5172显著抑制病毒复制[5]。MK-5172（0.4–35nM）处理GT1a（H77）复制子细胞72小时，MK-5172显著抑制HCV RNA复制（EC₉₀=0.9nM），且对NS5A耐药变异株仍保持抑制活性[6]。
在体内，MK-5172（10mg/kg/day）腹腔注射处理PD-1-mCherry-SMASh纯合敲入（KI）小鼠5天（从MC-38结肠腺癌细胞移植后第5天开始），MK-5172显著抑制肿瘤生长[7]。MK-5172（3mg/kg）口服给药处理糖尿病模型C57BL/6小鼠，每日一次连续3天，MK-5172显著恢复血糖稳态[8]。