更新于：2024-11-01

HCV E1

更新于：2024-11-01

基本信息

别名-

简介-

关联

丙型病毒性肝炎纳米颗粒疫苗(阿姆斯特丹大学)

靶点

HCV E1 x HCV E2

作用机制

HCV E1抑制剂 [+1]

在研机构

University of Amsterdam

原研机构

University of Amsterdam

在研适应症

病毒性肝炎

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 HCV E1 相关的临床结果

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100 项与 HCV E1 相关的转化医学

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0 项与 HCV E1 相关的专利（医药）

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项与 HCV E1 相关的文献（医药）

2023-12-14·Virus Evolution

HCV E1 influences the fitness landscape of E2 and may enhance escape from E2-specific antibodies

Article

作者: Bull, Rowena A ; McKay, Matthew R ; Quadeer, Ahmed Abdul ; Zhang, Hang

AbstractThe Hepatitis C virus (HCV) envelope glycoprotein E1 forms a non-covalent heterodimer with E2, the main target of neutralizing antibodies. How E1–E2 interactions influence viral fitness and contribute to resistance to E2-specific antibodies remain largely unknown. We investigate this problem using a combination of fitness landscape and evolutionary modeling. Our analysis indicates that E1 and E2 proteins collectively mediate viral fitness and suggests that fitness-compensating E1 mutations may accelerate escape from E2-targeting antibodies. Our analysis also identifies a set of E2-specific human monoclonal antibodies that are predicted to be especially resilient to escape via genetic variation in both E1 and E2, providing directions for robust HCV vaccine development.

2022-05-01·Cell Reports

Sites of vulnerability in HCV E1E2 identified by comprehensive functional screening

Article

作者: Mancini, Nicasio ; Rosenberg, Erin ; Law, Mansun ; Hernandez, Mayda ; Chambers, Ross ; Davidson, Edgar ; Kadash-Edmondson, Kathryn ; Clementi, Nicola ; Crowe, James E ; Pfaff-Kilgore, Jennifer M ; Bailey, Justin R ; Doranz, Benjamin J ; Castelli, Matteo

The E1 and E2 envelope proteins of hepatitis C virus (HCV) form a heterodimer that drives virus-host membrane fusion. Here, we analyze the role of each amino acid in E1E2 function, expressing 545 individual alanine mutants of E1E2 in human cells, incorporating them into infectious viral pseudoparticles, and testing them against 37 different monoclonal antibodies (MAbs) to ascertain full-length translation, folding, heterodimer assembly, CD81 binding, viral pseudoparticle incorporation, and infectivity. We propose a model describing the role of each critical residue in E1E2 functionality and use it to examine how MAbs neutralize infection by exploiting functionally critical sites of vulnerability on E1E2. Our results suggest that E1E2 is a surprisingly fragile protein complex where even a single alanine mutation at 92% of positions disrupts its function. The amino-acid-level targets identified are highly conserved and functionally critical and can be exploited for improved therapies and vaccines.

2022-02-10·Journal of Medicinal Chemistry1区 · 医学

Design, Synthesis, and Biological Evaluation of 2-((4-Bisarylmethyl-piperazin-1-yl)methyl)benzonitrile Derivatives as HCV Entry Inhibitors

1区 · 医学

Article

作者: Li, Jianrui ; Wang, Yixuan ; Li, Zhuorong ; Quan, Yanni ; Yang, Bo ; Li, Yanping ; Peng, Zonggen ; Tan, Jiali

Viral entry inhibitors are absent in hepatitis C virus (HCV) treatment regimens although a dozen direct-acting antiviral (DAA) drugs are available now. Based on a previously identified HCV entry inhibitor L0909, chemical space exploration and structure-activity relationship (SAR) studies led to the discovery of a new derived scaffold 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile. Several new scaffold derivatives exhibited higher in vitro anti-HCV activity at low nanomolar concentrations compared to L0909. A biological study indicated that the high potency of active derivatives 3d, 3h, and 3i was primarily driven by the inhibitory effect on the virus entry stage. Moreover, an SPR experiment confirmed that this class of derivatives might target the HCV E1 protein. Pharmacokinetic studies indicated that compounds 3d and 3i are orally available and long-lasting in rat plasma after oral administration to rats by a single dose of 15 mg/kg. In conclusion, this work provided a novel 2-((4-bisarylmethyl-piperazin-1-yl)methyl)benzonitrile chemotype deserving further investigation into its antiviral therapeutic potential.