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Antimicrob Agents Chemother. 2012 Aug;56(8):4277-88. doi: 10.1128/AAC.00473-12. Epub 2012 May 29.
Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation.
Cai D1, Mills C, Yu W, Yan R, Aldrich CE, Saputelli JR, Mason WS, Xu X, Guo JT, Block TM, Cuconati A, Guo H.
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Abstract
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a central role in viral infection and persistence and is the basis for viral rebound after the cessation of therapy, as well as the elusiveness of a cure even after extended treatment. Therefore, there is an urgent need for the development of novel therapeutic agents that directly target cccDNA formation and maintenance. By employing an innovative cell-based cccDNA assay in which secreted HBV e antigen is a cccDNA-dependent surrogate, we screened an in-house small-molecule library consisting of 85,000 drug-like compounds. Two structurally related disubstituted sulfonamides (DSS), termed CCC-0975 and CCC-0346, emerged and were confirmed as inhibitors of cccDNA production, with low micromolar 50% effective concentrations (EC(50)s) in cell culture. Further mechanistic studies demonstrated that DSS compound treatment neither directly inhibited HBV DNA replication in cell culture nor reduced viral polymerase activity in the in vitro endogenous polymerase assay but synchronously reduced the levels of HBV cccDNA and its putative precursor, deproteinized relaxed circular DNA (DP-rcDNA). However, DSS compounds did not promote the intracellular decay of HBV DP-rcDNA and cccDNA, suggesting that the compounds interfere primarily with rcDNA conversion into cccDNA. In addition, we demonstrated that CCC-0975 was able to reduce cccDNA biosynthesis in duck HBV-infected primary duck hepatocytes. This is the first attempt, to our knowledge, to identify small molecules that target cccDNA formation, and DSS compounds thus potentially serve as proof-of-concept drug candidates for development into therapeutics to eliminate cccDNA from chronic HBV infection.
PMID:
22644022
[PubMed - indexed for MEDLINE]
PMCID:
PMC3421587
Free PMC Article
抗菌试剂及化学。八月2012，56（8）：4277-88。 DOI：10.1128/ AAC.00473-12。 EPUB5月29日2012。
的二取代的磺酰胺化合物鉴定为B型肝炎病毒的特异性抑制剂共价闭合环状DNA形成。
蔡D1，米尔斯C，玉瓦，闫R，奥尔德里奇CE认证，Saputelli JR，梅森的WS，徐某某，郭JT座以旧换新，Cuconati A，郭H。
作者信息
摘要
乙型肝炎病毒（HBV）共价闭合环状DNA（cccDNA的）起着病毒感染和持续性核心作用，是基础，病毒反弹的治疗停止后，还有治愈的，即使延长治疗的难以捉摸。因此，目前迫切需要对新治疗剂直接靶向cccDNA的形成和维护的发展。通过采用创新的基于细胞的cccDNA检测中分泌的乙肝病毒e抗原是cccDNA的相关代孕，我们筛选了一个内部小分子库，包括85000类药性化合物。两个结构相关取代磺胺类（DSS），被称为CCC-0975和CCC-0346，并出现了被证实为cccDNA的产生的抑制剂，具有低微摩尔50％有效浓度（EC（50）S）在细胞培养。进一步的机制研究表明，DSS的化合物治疗不直接抑制HBV DNA复制在细胞培养中，也减少了病毒聚合酶的活性在体外源性聚合酶测定而同步地降低HBV cccDNA的和其假定的前体的水平，脱蛋白质松弛环状DNA（DP-rcDNA抑制）。然而，决策支持系统的化合物没有促进HBV DP-rcDNA抑制和cccDNA的细胞内的衰变，这表明这些化合物干扰主要与rcDNA抑制转化的cccDNA。此外，我们证明了CCC-0975能够降低cccDNA的生物合成鸭乙型肝炎病毒感染的原发性肝细胞的鸭子。这是第一次尝试，就我们所知，以确定小分子靶向cccDNA的形成，和DSS化合物从而有可能作为概念验证的候选药物发展为治疗以消除cccDNA的慢性HBV感染。
相关链接：
22644022
[考研 - 对MEDLINE收录]
PMCID：
PMC3421587
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发表于 2014-9-4 14:02
