Sanchez-Cespedes Javier, Moyer Crystal L, Whitby Landon R, Boger Dale L, Nemerow Glen R
Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 N. Torrey Pines Road, Mailcode IMM4, La Jolla, CA 92037, USA.
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, Mailcode BCC483, La Jolla, CA 92037, USA.
Antiviral Res. 2014 Aug;108:65-73. doi: 10.1016/j.antiviral.2014.05.010. Epub 2014 Jun 4.
The number of disseminated adenovirus (Ad) infections continues to increase mostly due to the growing use of immunosuppressive treatments. Recipients of solid organ or hematopoietic stem cell transplants, mainly in pediatric units, exhibit a high morbidity and mortality due to these infections. Unfortunately, there are no Ad-specific antiviral drugs currently approved for medical use. To address this situation, we used high-throughput screening (HTS) of synthetic small molecule libraries to identify compounds that restrict Ad infection. Among the more than 25,000 compounds screened, we identified a hit compound that significantly inhibited Ad infection. The compound (15D8) is a trisubstituted piperazin-2-one derivative that showed substantial antiviral activity with little or no cytotoxicity at low micromolar concentrations. Compound 15D8 selectively inhibits Ad DNA replication in the nucleus, providing a potential candidate for the development of a new class of antiviral compounds to treat Ad infections.
由于免疫抑制治疗的使用日益增加，播散性腺病毒（Ad）感染的数量持续上升。实体器官或造血干细胞移植受者，主要是儿科病房的患者，因这些感染而具有较高的发病率和死亡率。不幸的是，目前尚无经批准用于医学用途的Ad特异性抗病毒药物。为解决这一情况，我们利用合成小分子文库的高通量筛选（HTS）来鉴定能够限制Ad感染的化合物。在筛选的25000多种化合物中，我们鉴定出一种命中化合物，它能显著抑制Ad感染。该化合物（15D8）是一种三取代哌嗪-2-酮衍生物，在低微摩尔浓度下显示出显著的抗病毒活性，且几乎没有细胞毒性。化合物15D8选择性抑制细胞核中的Ad DNA复制，为开发一类新型抗病毒化合物以治疗Ad感染提供了一个潜在候选药物。
