<br>N-甲基金雀花碱硫代衍生物通过靶向病毒包膜蛋白和 NS2B-NS3 蛋白酶抑制登革热病毒,Bioorganic & Medicinal Chemistry Letters

当前位置： X-MOL 学术 › Bioorg. Med. Chem. Lett. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

N-甲基金雀花碱硫代衍生物通过靶向病毒包膜蛋白和 NS2B-NS3 蛋白酶抑制登革热病毒
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2024-01-18 , DOI: 10.1016/j.bmcl.2024.129623
Chen-Sheng Lin , Chih-Hao Lu , Tsai-Hsiu Lin , Yan-Tung Kiu , Ju-Ying Kan , Yu-Jen Chang , Ping-Yi Hung , Alena V. Koval'skaya , Dmitry O. Tsypyshev , Inna P. Tsypysheva , Cheng-Wen Lin

登革热病毒（DENV）是一种重大的全球健康威胁，每年在全球造成数百万例病例。开发针对登革热病毒的抗病毒药物一直是一项具有挑战性的工作。我们之前的研究从 19 (-)-金雀花碱衍生物库中鉴定出两种 (-)-金雀花碱衍生物的抗 DENV 特性，这些衍生物在 2-吡啶酮核心内含有取代基。本研究旨在通过研究β-甲基金雀花碱硫代（mCy thio）衍生物对DENV的抗病毒潜力，了解活性硫代衍生物抗病毒活性的分子机制，旨在扩展先前的研究。对 DENV-2 诱导的细胞病变效应和感染性的抑制测定表明，mCy 硫代衍生物 ((1R,5S)-3-methyl-1,2,3,4,5,6-hexaHydro-8H-1,5-methanopyrido [1,2-a][1,5]重氮辛-8-硫酮）和（(1S,5R)-3-甲基-2-硫代-1,2,3,4,5,6-六氢-8H- 1,5-methanopyrido[1,2-a][1,5]diazocin-8-one）被鉴定为对抗 DENV-1 和 DENV-2 的活性化合物。衍生物对 DENV-2 显示出强大的抗病毒活性，在不同细胞系中 EC 值范围为 0.002 至 0.005 μM。衍生物还表现出显着的针对 DENV-2 的抗病毒活性。研究发现，这些化合物在病毒生命周期的进入阶段（包括病毒附着）和进入后阶段都能有效抑制DENV-2。该研究还研究了这些化合物对 DENV-2 NS2B-NS3 蛋白酶活性的抑制作用。与 mCy thio 相比，衍生物表现出明显更强的抑制作用，揭示了其在进入和进入后阶段的双重抗病毒作用。分子对接模拟表明，mCy 硫代衍生物和 DENV E 蛋白的结构域 I 和 III 结合，以及 NS2B-NS3 蛋白酶的活性，表明它们与病毒存在分子相互作用。该研究证明了 β-甲基金雀花碱硫代衍生物对 DENV 的抗病毒功效。它为这些化合物与病毒靶蛋白之间的潜在相互作用提供了有价值的见解，这可能有助于开发 DENV 抗病毒药物。

"点击查看英文标题和摘要"

Inhibition of dengue viruses by N-methylcytisine thio derivatives through targeting viral envelope protein and NS2B-NS3 protease

Dengue virus (DENV) is a significant global health threat, causing millions of cases worldwide each year. Developing antiviral drugs for DENV has been a challenging endeavor. Our previous study identified anti-DENV properties of two (-)-cytisine derivatives contained substitutions within the 2-pyridone core from a pool of 19 (-)-cytisine derivatives. This study aimed to expand on the previous research by investigating the antiviral potential of -methylcytisine thio (mCy thio) derivatives against DENV, understanding the molecular mechanisms of antiviral activity for the active thio derivatives. The inhibitory assays on DENV-2-induced cytopathic effect and infectivity revealed that mCy thio derivatives ((1R,5S)-3-methyl-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocine-8-thione) and ((1S,5R)-3-methyl-2-thioxo-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one) were identified as the active compounds against both DENV-1 and DENV-2. Derivative displayed robust antiviral activity against DENV-2, with EC values ranging from 0.002 to 0.005 μM in different cell lines. Derivative also exhibited significant antiviral activity against DENV-2. The study found that these compounds are effective at inhibiting DENV-2 at both the entry stage (including virus attachment) and post-entry stages of the viral life cycle. The study also investigated the inhibition of the DENV-2 NS2B-NS3 protease activity by these compounds. Derivative demonstrated notably stronger inhibition compared to mCy thio , revealing its dual antiviral action at both the entry and post-entry stages. Molecular docking simulations indicated that mCy thio derivatives and bind to the domain I and III of the DENV E protein, as well as the active of NS2B-NS3 protease, suggesting their molecular interactions with the virus. The study demonstrates the antiviral efficacy of -methylcytisine thio derivatives against DENV. It provides valuable insights into the potential interactions between these compounds and viral target proteins, which could be useful in the development of antiviral drugs for DENV.

更新日期：2024-01-18

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南