...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine
【24h】

Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine

机译：衍生自2,5-二脱氧链烷胺的合成小分子弗林蛋白酶抑制剂

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Furin plays a crucial role in embryogenesis and homeostasis and in diseases such as Alzheimer's disease, cancer, and viral and bacterial infections. Thus, inhibition of furin may provide a feasible and promising approach for therapeutic intervention of f urin-mediated disease mechanisms. Here, we report on a class of small molecule furin inhibitors based on 2,5-dideoxystreptamine. Derivatization of 2,5-dideoxystreptamine by the addition of guanidinylated aryl groups yielded a set of furin inhibitors with nanomolar range potency against furin when assayed in a biochemical cleavage assay. Moreover, a subset of these furin inhibitors protected RAW 264.7 macrophage cells from toxicity caused by furin-dependent processing of anthrax protective antigen. These inhibitors were found to behave as competitive inhibitors of furin and to be relatively specific for furin. Molecular modeling revealed that these inhibitors may target the active site of furin as they showed site occupancy similar to the alkylating inhibitor decanoyl-Arg-Val-Lys-Arg-CH_2Cl. The compounds presented here are bona fide synthetic small molecule furin inhibitors that exhibit potency in the nanomolar range, suggesting that they may serve as valuable tools for studying furin action and potential therapeutics agents for furin-dependent diseases.
机译：弗林蛋白酶在胚胎发生和体内平衡以及阿尔茨海默氏病，癌症以及病毒和细菌感染等疾病中起着至关重要的作用。因此，抑制弗林蛋白酶可能为弗林蛋白酶介导的疾病机制的治疗干预提供一种可行且有希望的方法。在这里，我们报告基于2，5-二脱氧链烷胺的一类小分子弗林蛋白酶抑制剂。当在生化裂解试验中测定时，通过添加胍基化的芳基衍生化2，5-二脱氧链胺，产生了一套对弗林蛋白酶具有纳摩尔范围效力的弗林蛋白酶抑制剂。此外，这些弗林蛋白酶抑制剂的一个子集可保护RAW 264.7巨噬细胞免受因弗林蛋白酶依赖性处理炭疽保护性抗原而引起的毒性。发现这些抑制剂表现为弗林蛋白酶的竞争性抑制剂并且对弗林蛋白酶具有相对特异性。分子模型表明，这些抑制剂可能会靶向弗林蛋白酶的活性部位，因为它们显示出类似于烷基化抑制剂癸酰基-Arg-Val-Lys-Arg-CH_2Cl的位点占用。这里介绍的化合物是真正的合成小分子弗林蛋白酶抑制剂，在纳摩尔范围内显示出一定的效价，表明它们可以作为研究弗林蛋白酶作用的有价值的工具以及弗林蛋白酶依赖性疾病的潜在治疗剂。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号