Siebert Hans-Christian, Eckert Thomas, Bhunia Anirban, Klatte Nele, Mohri Marzieh, Siebert Simone, Kozarova Anna, Hudson John W, Zhang Ruiyan, Zhang Ning, Li Lan, Gousias Konstantinos, Kanakis Dimitrios, Yan Mingdi, Jiménez-Barbero Jesús, Kožár Tibor, Nifantiev Nikolay E, Vollmer Christian, Brandenburger Timo, Kindgen-Milles Detlef, Haak Thomas, Petridis Athanasios K
RI-B-NT-Research Institute of Bioinformatics and Nanotechnology, Schauenburgerstr. 116, 24118 Kiel, Germany.
Department of Chemistry and Biology, University of Applied Sciences Fresenius, Limburger Str. 2, 65510 Idstein, Germany.
Biomedicines. 2023 May 11;11(5):1421. doi: 10.3390/biomedicines11051421.
The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in different scientific fields, e.g., glycobiology, nanopharmacology, or nanomedicine. We correlated clinical biomedical data derived from patients in intensive care units with structural biology and biophysical data from NMR and/or CAMM (computer-aided molecular modeling). Consequently, new diagnostic and therapeutic approaches against SARS-CoV-2 were evaluated. Specifically, we tested the suitability of incretin mimetics with one or two pH-sensitive amino acid residues as potential drugs to prevent or cure long-COVID symptoms. Blood pH values in correlation with temperature alterations in patient bodies were of clinical importance. The effects of biophysical parameters such as temperature and pH value variation in relation to physical-chemical membrane properties (e.g., glycosylation state, affinity of certain amino acid sequences to sialic acids as well as other carbohydrate residues and lipid structures) provided helpful hints in identifying a potential Achilles heel against long COVID. In silico CAMM methods and in vitro NMR experiments (including P NMR measurements) were applied to analyze the structural behavior of incretin mimetics and SARS-CoV fusion peptides interacting with dodecylphosphocholine (DPC) micelles. These supramolecular complexes were analyzed under physiological conditions by H and P NMR techniques. We were able to observe characteristic interaction states of incretin mimetics, SARS-CoV fusion peptides and DPC membranes. Novel interaction profiles (indicated, e.g., by P NMR signal splitting) were detected. Furthermore, we evaluated GM1 gangliosides and sialic acid-coated silica nanoparticles in complex with DPC micelles in order to create a simple virus host cell membrane model. This is a first step in exploring the structure-function relationship between the SARS-CoV-2 spike protein and incretin mimetics with conserved pH-sensitive histidine residues in their carbohydrate recognition domains as found in galectins. The applied methods were effective in identifying peptide sequences as well as certain carbohydrate moieties with the potential to protect the blood-brain barrier (BBB). These clinically relevant observations on low blood pH values in fatal COVID-19 cases open routes for new therapeutic approaches, especially against long-COVID symptoms.
严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)/冠状病毒病2019(COVID-19)的全球大流行提供了一个积累大量生物医学数据集的平台,也带来了测试抗击这一流行病的新概念和策略的机遇与挑战。新的研究和分子医学方案可能会在不同的科学领域得到应用,例如糖生物学、纳米药理学或纳米医学。我们将重症监护病房患者的临床生物医学数据与来自核磁共振(NMR)和/或计算机辅助分子建模(CAMM)的结构生物学及生物物理数据进行了关联。因此,对针对SARS-CoV-2的新诊断和治疗方法进行了评估。具体而言,我们测试了具有一个或两个pH敏感氨基酸残基的肠促胰岛素类似物作为预防或治疗长期COVID症状的潜在药物的适用性。与患者体内温度变化相关的血液pH值具有临床重要性。诸如温度和pH值变化等生物物理参数相对于物理化学膜特性(例如糖基化状态、某些氨基酸序列对唾液酸以及其他碳水化合物残基和脂质结构的亲和力)的影响,为确定针对长期COVID的潜在致命弱点提供了有益的线索。应用计算机辅助分子建模方法和体外核磁共振实验(包括磷核磁共振测量)来分析肠促胰岛素类似物和SARS-CoV融合肽与十二烷基磷酸胆碱(DPC)胶束相互作用的结构行为。通过氢核磁共振和磷核磁共振技术在生理条件下对这些超分子复合物进行了分析。我们能够观察到肠促胰岛素类似物、SARS-CoV融合肽和DPC膜的特征性相互作用状态。检测到了新的相互作用谱(例如通过磷核磁共振信号分裂表明)。此外,我们评估了与DPC胶束复合的GM1神经节苷脂和唾液酸包被的二氧化硅纳米颗粒,以创建一个简单的病毒宿主细胞膜模型。这是探索SARS-CoV-2刺突蛋白与在半乳糖凝集素中发现的碳水化合物识别域具有保守pH敏感组氨酸残基的肠促胰岛素类似物之间结构-功能关系的第一步。所应用的方法有效地鉴定了具有保护血脑屏障(BBB)潜力的肽序列以及某些碳水化合物部分。这些关于致命COVID-19病例中低血液pH值的临床相关观察结果为新的治疗方法开辟了道路,特别是针对长期COVID症状的治疗方法。