Tollefson Ann E, Hussein Islam T M, Toth Karoly, Bowlin Terry L
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
Microbiotix, Inc., Worcester, MA, 01605, USA.
Antiviral Res. 2022 Dec;208:105431. doi: 10.1016/j.antiviral.2022.105431. Epub 2022 Oct 7.
Clusters of acute non HepA-E hepatitis cases in previously healthy children have been reported globally. At least, 1010 cases were identified in 35 countries, 5% of those cases required liver transplantation and 2% died. The exact cause is not yet known, but there is circumstantial evidence suggesting that human adenovirus F41 (HAdV-F41) might be playing a role. No antiviral drug has been approved for treating human adenovirus infections. Furthermore, HAdV-F41 is notoriously difficult to grow in cell culture, which hindered studying the efficacy of an antiviral compound against this virus. Here, we show that filociclovir (FCV), a nucleoside analog, is a potent inhibitor of HAdV-F41 in cell culture using 2 approaches, namely immunostaining of infected cells and virus yield reduction assay. The activity of FCV was compared to 3 other known antivirals: cidofovir (CDV), ganciclovir (GCV) and valganciclovir (VGCV). Among the 4 compounds examined in this study, FCV was the most potent, with an EC of 3.5 μM. These compounds can be ranked by potency as follows: FCV > CDV > GCV ≥ VGCV. In addition, FCV was 10-fold more potent than CDV in a virus yield reduction assay. This report provides timely and valuable methodologies to the research community for testing antivirals against HAdV-F41. Our findings also support the continued development of FCV for various therapeutic applications, including pediatric hepatitis, if a causal relationship is firmly established in the future.
全球范围内均有报道称，以往健康的儿童中出现了急性非甲 - 戊型肝炎病例集群。至少在35个国家发现了1010例病例，其中5%的病例需要进行肝移植，2%的病例死亡。确切病因尚不清楚，但有间接证据表明，人腺病毒F41（HAdV - F41）可能与之有关。目前尚无获批用于治疗人腺病毒感染的抗病毒药物。此外，HAdV - F41在细胞培养中极难生长，这阻碍了对抗病毒化合物针对该病毒的疗效研究。在此，我们表明，核苷类似物非环磷鸟苷（FCV）在细胞培养中通过两种方法，即对感染细胞进行免疫染色和病毒产量降低试验，是HAdV - F41的有效抑制剂。将FCV的活性与其他3种已知抗病毒药物进行了比较：西多福韦（CDV）、更昔洛韦（GCV）和缬更昔洛韦（VGCV）。在本研究中检测的4种化合物中，FCV最为有效，其半数有效浓度（EC）为3.5 μM。这些化合物按效力可排序如下：FCV > CDV > GCV ≥ VGCV。此外，在病毒产量降低试验中，FCV的效力比CDV高10倍。本报告为研究界提供了及时且有价值的方法，用于测试针对HAdV - F41的抗病毒药物。我们的研究结果还支持，如果未来能牢固确立因果关系，继续开发FCV用于各种治疗应用，包括小儿肝炎。
