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Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV‐1 Integrase
ChemMedChem ( IF 3.4 ) Pub Date : 2018-07-06 , DOI: 10.1002/cmdc.201800129 Susan E. Northfield 1 , Jerome Wielens 1, 2 , Stephen J. Headey 1 , Billy J. Williams‐Noonan 1 , Mark Mulcair 1 , Martin J. Scanlon 1 , Michael W. Parker 2, 3 , Philip E. Thompson 1 , David K. Chalmers 1
ChemMedChem ( IF 3.4 ) Pub Date : 2018-07-06 , DOI: 10.1002/cmdc.201800129 Susan E. Northfield 1 , Jerome Wielens 1, 2 , Stephen J. Headey 1 , Billy J. Williams‐Noonan 1 , Mark Mulcair 1 , Martin J. Scanlon 1 , Michael W. Parker 2, 3 , Philip E. Thompson 1 , David K. Chalmers 1
Affiliation
The p75 splice variant of lens epithelium‐derived growth factor (LEDGF) is a 75 kDa protein, which is recruited by the human immunodeficiency virus (HIV) to tether the pre‐integration complex to the host chromatin and promote integration of proviral DNA into the host genome. We designed a series of small cyclic peptides that are structural mimics of the LEDGF binding domain, which interact with integrase as potential binding inhibitors. Herein we present the X‐ray crystal structures, NMR studies, SPR analysis, and conformational studies of four cyclic peptides bound to the HIV‐1 integrase core domain. Although the X‐ray studies show that the peptides closely mimic the LEDGF binding loop, the measured affinities of the peptides are in the low millimolar range. Computational analysis using conformational searching and free energy calculations suggest that the low affinity of the peptides is due to mismatch between the low‐energy solution and bound conformations.
中文翻译:
与HIV-1整合酶复合的LEDGF整合酶识别环的环状六肽模拟物
晶状体上皮衍生生长因子(LEDGF)的p75剪接变体是一种75 kDa的蛋白质,由人类免疫缺陷病毒(HIV)募集以将整合前复合物束缚在宿主染色质上,并促进前病毒DNA整合入宿主基因组。我们设计了一系列小的环状肽,它们是LEDGF结合域的结构模拟物,可与整合酶相互作用作为潜在的结合抑制剂。在这里,我们介绍X射线晶体结构,NMR研究,SPR分析和结合到HIV-1整合酶核心域的四个环肽的构象研究。尽管X射线研究表明这些肽紧密模拟LEDGF结合环,但是这些肽的亲和力却处于较低的毫摩尔范围内。
更新日期:2018-07-06
中文翻译:
与HIV-1整合酶复合的LEDGF整合酶识别环的环状六肽模拟物
晶状体上皮衍生生长因子(LEDGF)的p75剪接变体是一种75 kDa的蛋白质,由人类免疫缺陷病毒(HIV)募集以将整合前复合物束缚在宿主染色质上,并促进前病毒DNA整合入宿主基因组。我们设计了一系列小的环状肽,它们是LEDGF结合域的结构模拟物,可与整合酶相互作用作为潜在的结合抑制剂。在这里,我们介绍X射线晶体结构,NMR研究,SPR分析和结合到HIV-1整合酶核心域的四个环肽的构象研究。尽管X射线研究表明这些肽紧密模拟LEDGF结合环,但是这些肽的亲和力却处于较低的毫摩尔范围内。