生物学杂志

生物学杂志 ›› 2023, Vol. 40 ›› Issue (6): 19-.doi: 10.3969/j.issn.2095-1736.2023.06.019

• 研究报告 • 上一篇    下一篇

环索奈德通过靶向HIV-1衣壳蛋白六聚体调节其体外装配

张　莉1,2， 张大为2， 包小峰1   

  1. 1. 南通大学 药学院， 南通 226001； 2. 江苏理工学院 生物信息与医药工程研究所， 常州 213001
  • 出版日期:2023-12-18 发布日期:2023-12-18
  • 通讯作者: 包小峰，博士，教授，研究方向为微生物与生化药学，E-mail:baoxi@ntu.edu.cn
  • 作者简介:张莉，硕士生，研究方向为微生物与生化药学，E-mail:294936467@qq.com
  • 基金资助:
    国家自然科学基金项目（31700297）； 南通市第六期江海英才市级培养专项

Ciclesonide acts as a moderator of HIV-1 capsid assembly by targeting the capsid hexamer

ZHANG Li1, 2, ZHANG Dawei2, BAO Xiaofeng1   

  1. 1. School of Pharmacy, Nantong University, Nantong 226001, China;
    2. Institute of Bioinformatics and Medical Engineering, Jiangsu University of Technology, Changzhou 213001, China
  • Online:2023-12-18 Published:2023-12-18

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摘要： 多肽CAI在HIV-1衣壳蛋白（CA）C末端的结合口袋可用来筛选CA蛋白装配调节剂。采用均相时间分辨荧光技术（HTRF）筛选399个化合物，发现1个小分子化合物环索奈德（ciclesonide）能够竞争性抑制十二肽CAI与CA蛋白C末端的结合，其半数抑制浓度IC50值为6.06 μmol/L。生物膜干涉技术（BLI）测量环索奈德与CA蛋白（单体和六聚体）的结合，环索奈德与CA六聚体的亲和力为159 nmol/L，远远大于其与CA单体的亲和力（KD=1.68 mmol/L）。衣壳蛋白体外装配实验表明，环索奈德能促进CA蛋白的装配，且具有浓度依赖性。分子模拟分析环索奈德与CA蛋白的结合模式，显示环索奈德与CA六聚体的相互作用发生在六聚体相邻亚基N末端-C末端的界面上，并与H67和L211两个残基形成氢键。研究表明，环索奈德是一种潜在的HIV-1衣壳装配调节剂。

关键词: 环索奈德, 衣壳装配, C端结构域, 人类免疫缺陷病毒1型, 均相时间分辨荧光技术

Abstract: The CAI-binding pocket in HIV-1 CA CTD can be used as target for antiviral development. In the present study, 399 compounds were screened against CA CTD-CAI interaction by a homogeneous time-resolved fluorescence (HTRF) assay. A compound, ciclesonide, was identified as inhibitor by competing with CAI binding to CA CTD (IC50=6.06 μmol/L). Biolayer interferometry assay demonstrated that ciclesonide preferentially binded to CA hexamer (KD=159 nmol/L) other than monomer (KD=1.68 mmol/L). In the CA assembly assay, ciclesonide could accelerate the assembly in a concentration-dependent manner. Molecular simulation suggested that ciclesonide could bind to NTD-CTD interface of adjacent protomers in the CA hexamer via H67 and L211 residues. These results indicated that ciclesonide was a potential moderator of HIV-1 capsid assembly.

Key words: ciclesonide, capsid assembly, C-terminal domain, human immunodeficiency virus 1, homogeneous time-resolved fluorescence

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