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维生素 D 受体激动剂对登革热病毒的活性。

Activity of vitamin D receptor agonists against dengue virus.

机构信息

Institute of Molecular Biosciences, Mahidol University, Salaya, 73170, Thailand.

School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211816, Jiangsu, China.

出版信息

Sci Rep. 2020 Jul 2;10(1):10835. doi: 10.1038/s41598-020-67783-z.

DOI:10.1038/s41598-020-67783-z
PMID:32616772
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7331731/
Abstract

Infections with the mosquito-transmitted dengue virus (DENV) are a pressing public health problem in many parts of the world. The recently released commercial vaccine for DENV has encountered some problems, and there is still no effective drug to treat infections. Vitamin D has a well characterized role in calcium and phosphorus homeostasis, but additionally has a role in the immune response to bacterial and viral pathogens. In this study a number of fused bicyclic derivatives of 1H-pyrrolo[1,2]imidazol-1-one with vitamin D receptor (VDR) agonist activity were evaluated for possible anti-DENV activity. The results showed that five of the compounds were able to significantly inhibit DENV infection. The most effective compound, ZD-3, had an EC value of 7.47 μM and a selective index of 52.75. The compounds were only effective when used as a post-infection treatment and treatment significantly reduced levels of infection, virus output, DENV protein expression and genome copy number. These results suggest that these VDR agonists have the potential for future development as effective anti-DENV agents.

摘要

在世界许多地区，蚊子传播的登革热病毒 (DENV) 感染是一个紧迫的公共卫生问题。最近推出的 DENV 商业疫苗遇到了一些问题，而且仍然没有有效的药物来治疗感染。维生素 D 在钙和磷的体内平衡中具有明确的作用，但它在对细菌和病毒病原体的免疫反应中也有作用。在这项研究中，评估了一些具有维生素 D 受体 (VDR) 激动剂活性的 1H-吡咯并[1,2]咪唑-1-酮融合双环衍生物，以评估它们是否具有抗 DENV 活性。结果表明，其中五种化合物能够显著抑制 DENV 感染。最有效的化合物 ZD-3 的 EC 值为 7.47 μM，选择性指数为 52.75。这些化合物只有在感染后治疗时才有效，治疗显著降低了感染水平、病毒产量、DENV 蛋白表达和基因组拷贝数。这些结果表明，这些 VDR 激动剂有可能作为有效的抗 DENV 药物进一步开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/f6af69186ef2/41598_2020_67783_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/8dbb99ecad2d/41598_2020_67783_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/fb18bf2ee12f/41598_2020_67783_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/709fe2726ff2/41598_2020_67783_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/c55f58f82ecb/41598_2020_67783_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/f6ce36e4d8b2/41598_2020_67783_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/916804643953/41598_2020_67783_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/41c2c6064917/41598_2020_67783_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/f6af69186ef2/41598_2020_67783_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/8dbb99ecad2d/41598_2020_67783_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/fb18bf2ee12f/41598_2020_67783_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/709fe2726ff2/41598_2020_67783_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/c55f58f82ecb/41598_2020_67783_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/f6ce36e4d8b2/41598_2020_67783_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/916804643953/41598_2020_67783_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/41c2c6064917/41598_2020_67783_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6544/7331731/f6af69186ef2/41598_2020_67783_Fig8_HTML.jpg

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