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基于结构的 - 磺酰基哌啶-3-羧酰胺类化合物的发现作为新型衣壳组装调节剂，可有效抑制 HBV 复制。

Structure-Based Discovery of -Sulfonylpiperidine-3-Carboxamides as Novel Capsid Assembly Modulators for Potent Inhibition of HBV Replication.

机构信息

Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.

出版信息

Viruses. 2022 Feb 8;14(2):348. doi: 10.3390/v14020348.

DOI:10.3390/v14020348
PMID:35215939
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8876525/
Abstract

As a key element during HBV replication, a nucleocapsid is considered a promising target for the treatment of chronic hepatitis B. The present study aimed to identify small molecules as novel capsid assembly modulators with antiviral activity. Structure-based virtual screening of an integrated compound library led to the identification of several types of HBV inhibitors. Among these inhibitors, -sulfonylpiperidine-3-carboxamides (SPCs) potently reduced the amount of secreted HBV DNA. Through structure-activity relationship studies, we identified an SPC derivative, namely, C-39, which exhibited the highest antiviral activity without causing cytotoxicity. Mechanism studies showed that C-39 dose-dependently inhibited the formation of HBV capsid, synthesis of cccDNA, e antigen (HBeAg), viral pregenomic RNA (pgRNA), and HBV DNA levels, thereby restraining HBV replication. In summary, SPCs represent a new class of capsid assembly modulators. Further optimization of SPCs is expected to obtain new antiviral drugs against HBV infection.

摘要

作为 HBV 复制过程中的关键元素，核衣壳被认为是治疗慢性乙型肝炎的有前途的靶标。本研究旨在鉴定具有抗病毒活性的新型衣壳组装调节剂的小分子。通过整合化合物库的基于结构的虚拟筛选，发现了几种类型的 HBV 抑制剂。在这些抑制剂中，-磺酰基哌啶-3-羧酰胺（SPCs）能有效减少分泌的 HBV DNA 的量。通过构效关系研究，我们鉴定出一种 SPC 衍生物，即 C-39，它具有最高的抗病毒活性而没有细胞毒性。机制研究表明，C-39 呈剂量依赖性抑制 HBV 衣壳的形成、cccDNA、e 抗原（HBeAg）、病毒前基因组 RNA（pgRNA）和 HBV DNA 水平，从而抑制 HBV 复制。总之，SPCs 代表了一类新的衣壳组装调节剂。进一步优化 SPCs 有望获得针对 HBV 感染的新型抗病毒药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/244e98c29f2b/viruses-14-00348-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/7c125a9b3b17/viruses-14-00348-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/26dd87510df1/viruses-14-00348-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/f42064e3ff93/viruses-14-00348-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/244e98c29f2b/viruses-14-00348-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/f780838a1c91/viruses-14-00348-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/33cdf6200275/viruses-14-00348-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/7c125a9b3b17/viruses-14-00348-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/f42064e3ff93/viruses-14-00348-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/02dd/8876525/244e98c29f2b/viruses-14-00348-g008.jpg

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Discovery of New Small Molecule Hits as Hepatitis B Virus Capsid Assembly Modulators: Structure and Pharmacophore-Based Approaches.发现新型小分子作为乙型肝炎病毒衣壳组装调节剂：结构和基于药效团的方法。
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Sulfamoylbenzamide-based Capsid Assembly Modulators for Selective Inhibition of Hepatitis B Viral Replication.
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