An Optimized Bioassay for Screening Combined Anticoronaviral Compounds for Efficacy against Feline Infectious Peritonitis Virus with Pharmacokinetic Analyses of GS-441524, Remdesivir, and Molnupiravir in Cats.
An Optimized Bioassay for Screening Combined Anticoronaviral Compounds for Efficacy against Feline Infectious Peritonitis Virus with Pharmacokinetic Analyses of GS-441524, Remdesivir, and Molnupiravir in Cats.
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DOI：
10.3390/v14112429
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发表时间：
2022-11-01
期刊：
影响因子：
--
通讯作者：
Murphy BG
中科院分区：
文献类型：
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作者：
Cook S;Wittenburg L;Yan VC;Theil JH;Castillo D;Reagan KL;Williams S;Pham CD;Li C;Muller FL;Murphy BG
猫传染性腹膜炎(FIP)是猫的一种致命疾病，目前缺乏获得许可和负担得起的疫苗或抗病毒治疗药物。该病有一系列的临床表现，包括渗出性(湿性)和非渗出性(干性)，两者都可能因神经或眼部受累而复杂化。猫冠状病毒(FCoV)生物型又称猫传染性腹膜炎病毒(FIPV)，是引起FIP的病原。本研究的目的是测定和比较病毒蛋白水解酶抑制剂GC376和尼马瑞韦与核苷类似物雷米昔韦、GS-441524、莫诺普拉韦和β-D-N4-羟胞苷(NHC；EIDD-1931)的体外抗病毒效果。使用优化的体外生物测定系统对这些抗病毒药物进行了功能评估。抗病毒药物被评估为针对FIPV血清I型和II型的单一疗法，以及针对FIPV血清II型的联合抗冠状病毒疗法(CACT)，这为所选组合的协同作用提供了证据。我们还测定了MPV、GS-441524和RDV在猫体内口服以及静脉注射RDV后的药代动力学特性。我们确定，口服MPV10 mg/kg，GS-441524和RDV 25 mg/kg，静脉注射RDV 7 mg/kg，血浆浓度高于相应的EC50值，GS-441514和RDV持续24小时以上。
Feline infectious peritonitis (FIP) is a fatal disease of cats that currently lacks licensed and affordable vaccines or antiviral therapeutics. The disease has a spectrum of clinical presentations including an effusive (“wet”) form and non-effusive (“dry”) form, both of which may be complicated by neurologic or ocular involvement. The feline coronavirus (FCoV) biotype, termed feline infectious peritonitis virus (FIPV), is the etiologic agent of FIP. The objective of this study was to determine and compare the in vitro antiviral efficacies of the viral protease inhibitors GC376 and nirmatrelvir and the nucleoside analogs remdesivir (RDV), GS-441524, molnupiravir (MPV; EIDD-2801), and β-D-N4-hydroxycytidine (NHC; EIDD-1931). These antiviral agents were functionally evaluated using an optimized in vitro bioassay system. Antivirals were assessed as monotherapies against FIPV serotypes I and II and as combined anticoronaviral therapies (CACT) against FIPV serotype II, which provided evidence for synergy for selected combinations. We also determined the pharmacokinetic properties of MPV, GS-441524, and RDV after oral administration to cats in vivo as well as after intravenous administration of RDV. We established that orally administered MPV at 10 mg/kg, GS-441524 and RDV at 25 mg/kg, and intravenously administered RDV at 7 mg/kg achieves plasma levels greater than the established corresponding EC50 values, which are sustained over 24 h for GS-441514 and RDV.