Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1
Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1
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DOI：
10.1021/acs.molpharmaceut.6b00156
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发表时间：
2016-07-01
影响因子：
4.9
通讯作者：
Postma, Almar
中科院分区：
文献类型：
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作者：
Danial, Maarten;Andersen, Anna H. F.;Postma, Almar
在这篇文章中，针对人类免疫缺陷病毒（HIV）的聚合物治疗剂库。采用可逆加成断裂链转移聚合法合成了不同摩尔质量的统计共聚物库。合成的聚合物包含侧链羟基和磺化侧链以及通过二硫化物自分解连接基连接的逆转录酶前药拉米夫定（3TC）。谷胱甘肽介导的3TC释放以及对HIV进入和聚合酶活性的抗病毒功效被证明。尽管有效的HIV进入抑制需要高度的聚合物磺化，但具有大约50%磺化单体的聚合物表现出有效的激酶非依赖性逆转录酶抑制。此外，磺化聚合物表现出对DNA聚合酶的活性，这表明这些聚合物可以表现出对广谱病毒的活性。总之，所述聚合物提供了抗HIV的三重活性武器库，其具有通过进入抑制的细胞外活性和通过基于激酶依赖性拉米夫定和基于激酶非依赖性磺化聚合物的抑制的细胞内活性。由于这些磺化共聚物很容易配制成凝胶，我们设想它们特别适合局部应用，以防止病毒，特别是HIV的粘膜传播。
In this article a library of polymeric therapeutic agents against the human immunodeficiency virus (HIV) is presented. The library of statistical copolymers of varied molar mass was synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. The synthesized polymers comprise pendent hydroxyl and sulfonated side chains as well as the reverse transcriptase prodrug lamivudine (3TC) attached via a disulfide self-immolative linker. The glutathione mediated release of 3TC is demonstrated as well as the antiviral efficacy against HIV entry and polymerase activity. Although a high degree of polymer sulfonation is required for effective HIV entry inhibition, polymers with approximately,similar to 50% sulfonated monomer demonstrated potent kinase independent reverse transcriptase inhibition. In addition, the sulfonated polymers demonstrate activity against DNA DNA polymerase, which suggests that these polymers may exhibit activity against a broad spectrum of viruses. In summary, the polymers described provide a triple-active arsenal against HIV with extracellular activity via entry inhibition and intracellular activity by kinase-dependent lamivudine-based and kinase-independent sulfonated polymer based inhibition. Since these sulfonated copolymers are easily formulated into gels, we envision them to be particularly suited for topical application to prevent the mucosal transmission of viruses, particularly HIV.