Riber Camilla Frich, Hinton Tracey M, Gajda Paulina, Zuwala Kaja, Tolstrup Martin, Stewart Cameron, Zelikin Alexander N
Department of Chemistry, Aarhus University , 8000 Aarhus, Denmark.
CSIRO-Health and Biosecurity Business Unit, Australian Animal Health Laboratory , Geelong, Vic 3220 Australia.
Mol Pharm. 2017 Jan 3;14(1):234-241. doi: 10.1021/acs.molpharmaceut.6b00826. Epub 2016 Nov 23.
The requirement for new antiviral therapeutics is an ever present need. Particularly lacking are broad spectrum antivirals that have low toxicity. We develop such agents based on macromolecular prodrugs whereby both the polymer chain and the drug released from the polymer upon cell entry have antiviral effects. Specifically, macromolecular prodrugs were designed herein based on poly(methacrylic acid) and ribavirin. Structure-function parameter space was analyzed via the synthesis of 10 polymer compositions varied by molar mass and drug content. Antiviral activity was tested in cell culture against both low and high pathogenic strains of influenza. Lead compounds were successfully used to counter infectivity of influenza in chicken embryos. The lead composition with the highest activity against influenza was also active against another respiratory pathogen, respiratory syncytial virus, providing opportunity to potentially treat infection by the two pathogens with one antiviral agent. In contrast, structure-function activity against the herpes simplex virus was drastically different, revealing limitations of the broad spectrum antiviral agents based on macromolecular prodrugs.
对新型抗病毒治疗药物的需求一直存在。尤其缺乏的是毒性低的广谱抗病毒药物。我们基于大分子前药开发此类药物，细胞进入后从聚合物释放的聚合物链和药物均具有抗病毒作用。具体而言，本文基于聚甲基丙烯酸和利巴韦林设计了大分子前药。通过合成10种摩尔质量和药物含量不同的聚合物组合物分析结构-功能参数空间。在细胞培养中针对低致病性和高致病性流感毒株测试了抗病毒活性。先导化合物成功用于对抗鸡胚中的流感感染性。对流感活性最高的先导组合物对另一种呼吸道病原体呼吸道合胞病毒也有活性，为用一种抗病毒药物潜在治疗两种病原体感染提供了机会。相比之下，对单纯疱疹病毒的结构-功能活性则截然不同，揭示了基于大分子前药的广谱抗病毒药物的局限性。
