Pritelivir, a helicase-primase inhibitor, has excellent in vitro and in vivo activity against human herpes simplex virus (HSV). Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 h after infection for 7 days with pritelivir or acyclovir. Both drugs were administered orally twice daily either alone or in combination. Dosages of pritelivir from 0.3 to 30 mg/kg reduced mortality (P < 0.001) against HSV-1, E-377. With an acyclovir resistant HSV-1, 11360, pritelivir at 1 and 3 mg/kg increased survival (P < 0.005). With HSV-2, MS infected mice, all dosages higher than the 0.3 mg/kg dose of pritelivir were effective (P < 0.005). For acyclovir resistant HSV-2, strain 12247, pritelivir dosages of 1–3 mg/kg significantly improved survival (P < 0.0001). Combination therapies of pritelivir at 0.1 or 0.3 mg/kg/dose with acyclovir (10 mg/kg/dose) were protective (P < 0.0001) when compared to the vehicle treated group against HSV-2, strain MS (in line with previous data using HSV-1). An increased mean days to death (P < 0.05) was also observed and was indicative of a potential synergy. Pharmacokinetic studies were performed to determine pritelivir concentrations and a dose dependent relationship was found in both plasma and brain samples regardless of infection status or time of initiation of dosing. In summary, pritelivir was shown to be active when treatment was delayed to 72 h post viral inoculation and appeared to synergistically inhibit mortality in this model in combination with acyclovir. We conclude pritelivir has potent and resistance-breaking antiviral efficacy with potential for the treatment of potentially life-threatening HSV type 1 and 2 infections, including herpes simplex encephalitis.

Pritelivir 是一种解旋酶引物酶抑制剂，在体外和体内均具有出色的抗人单纯疱疹病毒 (HSV) 活性。致死感染 1 型或 2 型 HSV（包括阿昔洛韦耐药株）的小鼠在感染 72 小时后用普替利韦或阿昔洛韦治疗 7 天。两种药物单独或联合口服，每日两次。 0.3 至 30 mg/kg 的普替利韦剂量可降低 HSV-1、E-377 的死亡率 (P < 0.001)。对于阿昔洛韦耐药的 HSV-1, 11360，1 和 3 mg/kg 的普替利韦可增加存活率 (P < 0.005)。对于HSV-2、MS感染的小鼠，所有高于0.3mg/kg剂量的普替利韦的剂量均有效(P<0.005)。对于阿昔洛韦耐药的 HSV-2（12247 株），1-3 mg/kg 的普替利韦剂量可显着提高生存率（P < 0.0001）。与载体治疗组相比，0.1 或 0.3 mg/kg/剂量的普替利韦与阿昔洛韦（10 mg/kg/剂量）的联合治疗对 HSV-2、MS 株具有保护性（P < 0.0001）（与之前的数据一致）使用 HSV-1）。还观察到平均死亡天数增加（P < 0.05），这表明存在潜在的协同作用。进行药代动力学研究以确定普替利韦浓度，并且在血浆和脑样本中发现剂量依赖性关系，无论感染状态或开始给药时间如何。总之，当治疗延迟至病毒接种后 72 小时时，普替利韦显示出活性，并且与阿昔洛韦联合使用该模型似乎可以协同抑制死亡率。我们的结论是，pritelivir 具有有效且突破耐药性的抗病毒功效，有可能用于治疗可能危及生命的 1 型和 2 型 HSV 感染，包括单纯疱疹脑炎。