摘要
背景:核苷酸是具有生物医学重要性的嵌合化合物,携带DNA碱基锚定在肽骨干上,并确定了与核酸结合的能力。然而,它们与参与社会相关性病理的蛋白质相互作用的能力仍然是一个需要研究的特征。当前全球对COVID-19流行病的担忧形势迫切需要新型抗SARSCoV- 2分子武器的研究,其发现可借助计算机预测研究。 目的:本工作的目的是通过光谱方法探索基于l -二氨基丙酸的胸腺嘧啶核肽的新特征,包括构象方面及其结合蛋白的能力,从牛血清白蛋白(BSA)作为模型蛋白开始。此外,考虑到靶向病毒蛋白在当前抗COVID-19的重要性,我们在计算机上评估了核酸肽与一些最相关的冠状病毒蛋白靶点的相互作用。 方法:首先,我们通过圆二色性(CD)研究了这种胸腺嘧啶核肽在温度下的构象行为:我们观察了CD的光谱变化,特别是在15到35°C范围内。对核苷酸固体样品进行了扫描电镜分析。此外,以牛血清白蛋白作为模型蛋白进行CD结合和计算机初步研究。此外,分子对接以一些主要的SARS-CoV-2蛋白为目标。结果:温度依赖性的CD行为反映了不同温度下核肽的三维重排,与低温下堆叠结构相比,在更高的温度下其发色团的溶剂暴露率更高。核肽样品在固体状态下的SEM分析显示为粒状形貌,具有较低的粗糙度和一些螺纹结构。此外,我们通过光谱研究发现,修饰后的多肽通过诱导蛋白二级结构发生显著变化而与白蛋白靶点结合。 结论:CD和初步的硅研究表明,核苷酸与BSA蛋白结合的方式不同,具有较高的亲和力,结合能量评分低于-11千卡/mol。有趣的是,一项对3CLpro和其他SARS-CoV-2蛋白靶点进行的预测研究表明,核酸肽具有以良好亲和力结合病毒的主要蛋白酶和其他相关靶点的潜在能力,包括依赖RNA的RNA聚合酶,特别是与RNA、木瓜样蛋白酶、和冠状病毒解旋酶在核酸结合位点。
关键词: 核酸肽、SEM、CD、蛋白结合、RNA -蛋白复合物、COVID-19、SARS-CoV-2
Current Medicinal Chemistry
Title:Evidence of Protein Binding by a Nucleopeptide Based on a Thyminedecorated L-Diaminopropanoic Acid through CD and In Silico Studies
Volume: 28 Issue: 24
关键词: 核酸肽、SEM、CD、蛋白结合、RNA -蛋白复合物、COVID-19、SARS-CoV-2
摘要:
Background: Nucleopeptides are chimeric compounds of biomedical importance carrying DNA nucleobases anchored to peptide backbones with the ascertained capacity to bind nucleic acids. However, their ability to interact with proteins involved in pathologies of social relevance is a feature that still requires investigation. The worrying situation currently observed worldwide for the COVID-19 pandemic urgently requires the research on novel anti-SARSCoV- 2 molecular weapons, whose discovery can be aided by in silico predictive studies.
Objective: The aim of this work is to explore by spectroscopic methods novel features of a thymine-bearing nucleopeptide based on L-diaminopropanoic acid, including conformational aspects as well as its ability to bind proteins, starting from bovine serum albumin (BSA) as a model protein. Moreover, in consideration of the importance of targeting viral proteins in the current fight against COVID-19, we evaluated in silico the interaction of the nucleopeptide with some of the most relevant coronavirus protein targets.
Methods: First, we investigated via circular dichroism (CD) the conformational behaviour of this thymine-bearing nucleopeptide with temperature: we observed CD spectral changes, particularly passing from 15 to 35 °C. Scanning Electron Microscopy (SEM) analysis of the nucleopeptide was also conducted on nucleopeptide solid samples. Additionally, CD binding and preliminary in silico investigations were performed with BSA as a model protein. Moreover, molecular dockings were run using as targets some of the main SARS-CoV-2 proteins.
Results: The temperature-dependent CD behaviour reflected the three-dimensional rearrangement of the nucleopeptide at different temperatures, with higher exposure to the solvent of its chromophores at higher temperatures compared to a more stacked structure at a low temperature. SEM analysis of nucleopeptide samples in the solid-state showed a granular morphology, with a low roughness and some thread structures. Moreover, we found through spectroscopic studies that the modified peptide bound the albumin target by inducing significant changes to the protein secondary structure.
Conclusion: CD and preliminary in silico studies suggested that the nucleopeptide bound the BSA protein with high affinity according to different binding modes, as testified by binding energy scores lower than -11 kcal/mol. Interestingly, a predictive study performed on 3CLpro and other SARS-CoV-2 protein targets suggested the potential ability of the nucleopeptide to bind with good affinity the main protease of the virus and other relevant targets, including the RNAdependent RNA polymerase, especially when complexed with RNA, the papain-like protease, and the coronavirus helicase at the nucleic acid binding site.
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Evidence of Protein Binding by a Nucleopeptide Based on a Thyminedecorated L-Diaminopropanoic Acid through CD and In Silico Studies, Current Medicinal Chemistry 2021; 28 (24) . https://dx.doi.org/10.2174/0929867328666210201152326
DOI https://dx.doi.org/10.2174/0929867328666210201152326 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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