Smith Anton A A, Zuwala Kaja, Kryger Mille B L, Wohl Benjamin M, Guerrero-Sanchez Carlos, Tolstrup Martin, Postma Almar, Zelikin Alexander N
Department of Chemistry Aarhus University , Aarhus C 8000 , Denmark . Email:
Aarhus University Hospital , Aarhus C , Denmark.
Chem Sci. 2015 Jan 1;6(1):264-269. doi: 10.1039/c4sc02754j. Epub 2014 Sep 16.
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) represent tremendous healthcare burdens with a large proportion of patients hosting the two viruses at the same time. An altered hepatic function and immunity as well as cross-interference of drugs make treatment of co-infection increasingly challenging. Herein we report the first design of macromolecular prodrugs (MP) with concurrent success in fighting HIV and alleviating hepatitis (liver inflammation). To achieve this, polymer compositions were systematically screened in a broad range of molar mass and content of ribavirin - a broad spectrum antiviral agent. For the first time, we report that ribavirin is efficacious in fighting HIV and in the form of MP, the treatment is safe, both in terms of lack of association of ribavirin with red blood cells and lack of toxicity upon cellular internalization. The lead polymer compositions were also potent in anti-inflammatory assays with relevance to viral hepatitis - thus making up formulations with potential for treatment of co-infection with HIV and HCV.
人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）给医疗保健带来了巨大负担，很大一部分患者同时感染这两种病毒。肝功能和免疫力的改变以及药物的交叉干扰使得合并感染的治疗越来越具有挑战性。在此，我们报告了首例大分子前药（MP）的设计，该设计在对抗HIV和减轻肝炎（肝脏炎症）方面均取得了成功。为实现这一目标，我们在广泛的摩尔质量范围和利巴韦林（一种广谱抗病毒剂）含量内系统筛选了聚合物组合物。我们首次报告，利巴韦林在对抗HIV方面有效，且以MP形式存在时，治疗是安全的，这体现在利巴韦林与红细胞无关联以及细胞内化后无毒性。领先的聚合物组合物在与病毒性肝炎相关的抗炎试验中也表现出效力——从而构成了具有治疗HIV和HCV合并感染潜力的制剂。
