莱纳卡巴维尔在未成熟的HIV-1中具有不同的向部位,并与成熟抑制剂Bevirimat同时结合
Chunxiang Wu1, Megan E Meuser1, Juan S Rey2
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06511, United States.
Journal of the American Chemical Society
|November 6, 2025
概括
新的冷EM结构揭示了HIV-1抑制剂bevirimat (BVM) 和lenacapavir (LEN) 的作用. 这些发现澄清了BVM和LEN
科学领域:
- 结构生物学
- 病毒学
- 药物发现
背景情况:
- 人类免疫缺陷病毒1型 (HIV-1) 的成熟是抗病毒疗法的关键目标.
- 目前的HIV-1抑制剂如贝维里马特 (BVM) 和莱纳卡巴维尔 (LEN) 显示有效性,但由于结构数据有限,其确切的作用机制尚未完全理解.
- 对于未成熟的Gag格子和成熟的LEN,缺乏高分辨率的结构信息,从而阻碍了对其抑制作用的完全理解.
研究的目的:
- 确定HIV-1的in situ冷电子显微镜 (冷EM) 结构,其中BVM和LEN与未成熟的Gag网格结合在一起.
- 阐明LEN对未成熟和成熟的HIV-1颗粒的独特结合方式和结构影响.
- 为BVM与Gag网格的相互作用提供一个准确的结构模型,独立于LEN.
主要方法:
- 从哺乳动物细胞中产生穿孔病毒样颗粒 (VLP),以模仿原生HIV-1结构.
- 应用现场冷电子显微镜 (cryo-EM) 来捕获受抑制剂结合的VLP的高分辨率结构数据.
- 计算建模和结构分析以解释抑制剂-Gag晶格相互作用.
主要成果:
- 第一个高分辨率的冷EM结构与BVM和LEN复合原生未成熟的HIV-1粒子.
- 证明LEN与未成熟的Gag格子结合的方式与其与成熟的状体的相互作用不同.
- 观察LEN诱导的状蛋白 (CA) 变化和Gag晶格结构的变化,可能影响病毒成熟.
- 将BVM与Gag网格结合的精细结构模型,显示独立于LEN的相互作用.
结论:
- LEN具有双重向,与未成熟和成熟的HIV-1结构成分相互作用.
- 对LEN和BVM结合的结构洞察力为其抗病毒机制提供了更深入的理解.
- 这些发现为下一代HIV-1抑制剂的合理设计提供了有价值的结构蓝图.
更多相关视频
10:29Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
2.1K
11:34A Competent Hepatocyte Model Examining Hepatitis B Virus Entry through Sodium Taurocholate Cotransporting Polypeptide as a Therapeutic Target
Published on: May 10, 2022
2.6K
相关概念视频
02:33Retroviruses
14.6K
Retroviruses and retrotransposons both insert copies of their genetic elements into the genome of the host cell. Thus, the viral genes are passed on when the host genome is replicated or translated. A typical retroviral DNA sequence contains 3-4 genes that encode the different proteins required for its structural assembly and function as a molecular parasite. This DNA is transcribed into a single mRNA, which is very similar in structure to conventional mRNAs, i.e., it is capped at the 5’...
14.6K
01:10Retrovirus Life Cycles
49.2K
Retroviruses have a single-stranded RNA genome that undergoes a special form of replication. Once the retrovirus has entered the host cell, an enzyme called reverse transcriptase synthesizes double-stranded DNA from the retroviral RNA genome. This DNA copy of the genome is then integrated into the host’s genome inside the nucleus via an enzyme called integrase. Consequently, the retroviral genome is transcribed into RNA whenever the host’s genome is transcribed, allowing the...
49.2K
01:29Subviral Agents
488
Subviral agents are infectious entities that resemble viruses but lack one or more viral components, such as a capsid or essential replication machinery. These agents include viroids, prions, and satellites, each possessing distinct structural and functional characteristics that influence their mode of infection and replication.Viroids are the simplest subviral agents, consisting of circular, single-stranded RNA molecules without a protein coat. They exclusively infect plants, relying entirely...
488