Brivudine (Bromovinyldeoxyuridine) is a thymidine analogue and an inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) replication[1, 2]. Brivudine is converted to its 5'-triphosphate form by viral thymidine kinase (TK), which can be incorporated into viral DNA, inhibiting viral DNA polymerase and inducing chain breaks[3, 4]. Brivudine is an inhibitor of thymidylate synthase (TS). Brivudine can bind to TS after in vitro phosphorylation by TK[5].
In vitro, when Brivudine (0.0625, 0.125, 0.25, 0.5, 1.0µg/mL) was used to treat 1:1 mixed culture of neural progenitor cells carrying the HSV-TK suicide gene (HSV-TK+ NPCs) and wild-type neural progenitor cells (WT-mCherry+ NPCs, which were not transferred with the HSV-TK gene but were labeled with red fluorescent protein) for 96h, a significant decrease in the number of attached and growing WT-mCherry+ NPCs was observed, indicating that Brivudine not only eliminated HSV-TK+ NPCs, but also effectively killed the surrounding wild-type cells through the bystander effect[6].
References:
[1] De Clercq E, Desgranges C, Herdewijn P, et al. Synthesis and antiviral activity of (E)-5-(2-bromovinyl) uracil and (E)-5-(2-bromovinyl) uridine[J]. Journal of medicinal chemistry, 1986, 29(2): 213-217.
[2] Kulikowski T. Structure-activity relationships and conformational features of antiherpetic pyrimidine and purine nucleoside analogues. A review[J]. Pharmacy World and Science, 1994, 16(2): 127-138.
[3] Deval J. Antimicrobial strategies: inhibition of viral polymerases by 3′-hydroxyl nucleosides[J]. Drugs, 2009, 69(2): 151-166.
[4] Yin M T, Brust J C M, Tieu H V, et al. Antiherpesvirus, Anti‐Hepatitis Virus, and Anti‐Respiratory Virus Agents[J]. Clinical virology, 2009: 217-264.
[5] Hew K, Dahlroth S L, Veerappan S, et al. Structure of the varicella zoster virus thymidylate synthase establishes functional and structural similarities as the human enzyme and potentiates itself as a target of brivudine[J]. PLoS One, 2015, 10(12): e0143947.
[6] Lou Z, Post A, Rodgers C E, et al. Neural progenitor cells expressing herpes simplex virus-thymidine kinase for ablation have differential chemosensitivity to brivudine and ganciclovir[J]. Frontiers in Cellular Neuroscience, 2021, 15: 638021.
Brivudine (Bromovinyldeoxyuridine)是一种胸腺嘧啶类似物，也是单纯疱疹病毒 1型（HSV-1）和水痘-带状疱疹病毒（VZV）病毒复制的抑制剂[1, 2]。Brivudine在病毒胸苷激酶（TK）的作用下转化为5'-三磷酸形式后，能够被掺入病毒DNA，抑制病毒DNA聚合酶并诱导链断裂[3, 4]。Brivudine是胸苷酸合酶（thymidylate synthase, TS）的抑制剂，Brivudine在TK的体外磷酸化后能够与TS结合[5]。
在体外，Brivudine（0.0625, 0.125, 0.25, 0.5, 1.0µg/mL）处理1:1混合培养的携带HSV-TK自杀基因的神经祖细胞（HSV-TK+ NPCs）和野生型神经祖细胞（WT-mCherry+ NPCs，没有被转入HSV-TK基因，但被标记了红色荧光蛋白）96h，观察到附着生长的WT-mCherry+ NPCs数量显著减少，表明Brivudine不仅清除了HSV-TK+ NPCs，还通过旁观者效应有效杀伤了周围的野生型细胞[6]。