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一种治疗丙型肝炎病毒的方法:基于反义寡核苷酸的候选衣壳抑制剂的计算机设计。

A therapeutic approach for the hepatitis C virus: in silico design of an antisense oligonucleotide-based candidate capsid inhibitor.

机构信息

Department of Medical Biology and Genetics, Institute of Health Sciences, Marmara University, Istanbul, Turkey.

Faculty of Medicine, Department of Medical Biology, Marmara University, Istanbul, Turkey.

出版信息

Virus Genes. 2024 Oct;60(5):446-454. doi: 10.1007/s11262-024-02088-1. Epub 2024 Jul 31.

DOI:10.1007/s11262-024-02088-1
PMID:39083128
Abstract

Direct-acting antiviral (DAA) drugs have been shown to effectively reduce viral load and cure a high proportion of hepatitis C virus (HCV) infections. However, costs associated with the course of therapy and any possible adverse effects should also be considered. It is important to acknowledge, moreover, that certain groups may not be eligible for treatment. Given that there is currently no approved vaccine for HCV infection, the need for an effective, safe, and accessible treatment remains a crucial priority. The aim of this study is to develop an antisense oligonucleotide (ASO)-based therapeutic drug that can inhibit HCV capsid. After analyzing 817 HCV capsid protein mRNA sequences using the NCBI Virus Data Portal, a conserved region of 7 nucleotides (nt) was identified in all genotypes (1-7). However, because of its high GC% content, this region is not a suitable target for ASO. Conversely, the other highly conserved region, which is only 8 nt long, was preserved in 801 datasets after removing missing and differing sequence data. The candidate ASO was then investigated using computer simulations to assess its potential. Thus, it is possible that the ASO sequence consisting of 8 nt could be a viable therapeutic target for the inhibition of HCV capsid. Furthermore, the 7 nt sequence, which is conserved in all datasets, may be targeted using alternative strategies in lieu of ASO-based targeting.

摘要

直接作用抗病毒 (DAA) 药物已被证明能有效降低病毒载量并治愈很大比例的丙型肝炎病毒 (HCV) 感染。然而,还应考虑与治疗过程相关的成本和任何可能的不良反应。此外,还需要认识到某些群体可能不符合治疗条件。鉴于目前尚无 HCV 感染的批准疫苗,因此需要一种有效、安全且易于获得的治疗方法仍然是当务之急。本研究旨在开发一种基于反义寡核苷酸 (ASO) 的治疗药物,以抑制 HCV 衣壳。通过使用 NCBI Virus Data Portal 分析 817 个 HCV 衣壳蛋白 mRNA 序列后,在所有基因型 (1-7) 中均鉴定到一个 7 个核苷酸 (nt) 的保守区域。然而,由于其高 GC%含量,该区域不适合作为 ASO 的靶标。相反,在去除缺失和不同序列数据后,另一个只有 8 个核苷酸长的高度保守区域在 801 个数据集得到了保留。然后使用计算机模拟研究候选 ASO,以评估其潜力。因此,由 8 个核苷酸组成的 ASO 序列可能是抑制 HCV 衣壳的可行治疗靶标。此外,在所有数据集中保守的 7 个核苷酸序列可能可以使用替代策略进行靶向,而不是基于 ASO 的靶向。

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本文引用的文献

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Bepirovirsen (GSK3228836) in chronic hepatitis B infection: an evaluation of phase II progress.贝匹昔洛韦(GSK3228836)治疗慢性乙型肝炎感染:Ⅱ期进展评估。
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The burden of hepatitis C virus in the world, China, India, and the United States from 1990 to 2019.1990 年至 2019 年全球、中国、印度和美国丙型肝炎病毒负担。
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Breakthroughs in hepatitis C research: from discovery to cure.
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Liver-Targeted Delivery of Oligonucleotides with N-Acetylgalactosamine Conjugation.通过N-乙酰半乳糖胺偶联实现寡核苷酸的肝脏靶向递送
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HCV virology and diagnosis.丙型肝炎病毒的病毒学与诊断
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Site-specific incorporation of 5'-methyl DNA enhances the therapeutic profile of gapmer ASOs.在特定位置掺入 5'-甲基化 DNA 可增强 gapmer ASO 的治疗效果。
Nucleic Acids Res. 2021 Feb 26;49(4):1828-1839. doi: 10.1093/nar/gkab047.
8
Update on Hepatitis C Epidemiology: Unaware and Untreated Infected Population Could Be the Key to Elimination.丙型肝炎流行病学最新情况:未被察觉和未接受治疗的感染人群可能是消除丙肝的关键。
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