低聚苯酰胺蛋白质α-螺旋模拟物的合成

非肽小分子α-螺旋模拟物的设计与合成是蛋白质相互作用抑制剂研发的一个重要方向。该方法通过设计、合成有机小分子化合物来模拟蛋白质相互作用界面热点区域(hot-spot)的α-螺旋结构。利用模拟物与相应蛋白质结合,从而阻断特定蛋白质-蛋白质之间的相互作用,最终达到治疗相应疾病的目的。本文以低聚苯酰胺为骨架,设计、合成了以阿司匹林为母体的蛋白质α-螺旋模拟物。     

靶向于Galectin-10蛋白的哮喘抑制剂设计

Galectin-10（Gal10）存在于人类嗜酸性细胞中,可经历相变成为晶体而诱发哮喘疾病。通过分子动力学模拟方法结合分子力学-泊松-玻尔兹曼方程-表面积计算自由能分解方法解析Gal10蛋白与溶晶抗体相互作用,发现Gal10蛋白与溶晶抗体结合主要依靠疏水相互作用驱动,对结合起最有利贡献的氨基酸残基包括Gal10蛋白的Y69、K117、D113、E68、I116、H114和溶晶抗体的W53-H、Y104-H、N97-L、K55-L、Y93-L、R100-H。以此为基础,构建Gal10蛋白与溶晶抗体相互作用的亲和结合模型,以设计抑制剂并构建序列为WXYXXNXY的抑制剂库,利用分子对接、分子动力学模拟、构象比对等方法,最终确定获得WGYGWNGY等潜在高效哮喘抑制剂。     

离子液体表面活性剂的合成与应用(Ⅺ)——与生物活性分子的相互作用

从3方面综述了离子液体表面活性剂与生物活性分子的相互作用。亲油性的离子液体表面活性剂可与β-环糊精形成1:1,1:2或2:1型包合物,而亲水性的离子液体表面活性剂不能与β-环糊精形成包合物,这些包合物的形成影响了表面活性剂的cmc和在界面的吸附。离子液体表面活性剂能够与牛血清蛋白、β-酪蛋白、溶菌酶等蛋白质相互作用,影响蛋白质的分子构型以及在油/水界面的吸附状态。离子液体表面活性剂与DNA的相互作用主要来源于静电吸引和疏水作用。     

表面活性剂与蛋白质相互作用的研究进展

综述了表面活性剂与蛋白质的相互作用以及该领域最新的研究方法和研究成果。从荧光技术在研究表面活性剂－蛋白质相互作用中的应用为出发点，介绍了表面活性剂与蛋白质相互作用所形成的复合物的结构及相互作用过程中蛋白质结构的变化；在阐述表面活性剂－蛋白质相同电荷混合体系及相反电荷混合体系的不同相行为特征的同时，介绍了NMR弛豫技术和冷冻蚀刻电镜在研究表面活性剂与蛋白质相互作用中的应用；表面活性剂－蛋白质混合溶液的界面吸附行为的研究以非离子表面活性剂与蛋白质的相互作用为主线，介绍了表面活性剂－蛋白质混合溶液界面吸附的2种机理，以及LB膜技术和流变学研究方法在研究表面活性剂－蛋白质相互作用中的应用。     

金纳米材料与蛋白质相互作用研究进展

金纳米材料是一种具有独特物理化学性质的纳米材料,和光相互作用产生表面等离子共振效应。金纳米材料在生物、医药、催化和传感等领域广阔的应用前景。在纳米材料大规模应用之前,深入研究和理解纳米材料的生物学性质非常必要。纳米材料和生物分子(尤其是蛋白质)的相互作用,是理解和评价其生物相学性质和生理功能的关键。综述了金纳米材料与蛋白质的相互作用,从蛋白质的种类和结构、金纳米材料的尺寸、形貌以及表面化学等方面阐述了这一基本科学问题。     

蛋白质分子与固体表面相互作用的分子模拟

蛋白质分子和固体表面的相互作用在与生物有关的材料以及工程领域有着重要的影响.两者相互作用的复杂性使得单纯依靠实验无法得到完整的信息.利用分子模拟，从分子尺度上对蛋白质和固体表面的相互作用进行研究，有助于更清楚地了解决定蛋白质在固体表面行为的原因.本文综述了蛋白质与固体表面相互作用的分子模拟研究，主要介绍有关蛋白质模型的选择、表面对蛋白质吸附能力的机理以及蛋白质在吸附表面的取向和构型变化的研究现状和成果.     

金属配合物与蛋白质弱相互作用荧光法研究进展

金属配合物与蛋白质等生物分子的弱相互作用研究,是生物学家和化学家共同关注的课题,而荧光光谱法在推测金属配合物和蛋白质之间的弱相互作用方面表现出较大的优势。文章对近年来金属配合物与蛋白质的弱相互作用荧光光谱法研究进展进行了综述,并提出了该研究领域的新动向。     

蛋白质与有机小分子反应机理的研究

评述了有机小分子与蛋白质的相互作用机理的研究结果和研究方法。     

蛋白质微阵列的制备及其在病原体检测中的应用

蛋白质微阵列是近年发展起来的新技术,具有高通量、微型化及自动化等优点,能够高通量地测定蛋白质的存在及其生物活性,也可以测定蛋白质与生物大分子之间的相互作用。本文介绍了蛋白质微阵列的制备方法及其在病原体毒力、耐药性及免疫原性等方面的应用。     

蛋白质直接电化学的研究分析

蛋白质在电极表面具有良好的取向是实现蛋白质，电极之间直接快速电子传递的前提，因此采用适当的方法在电极表面固定蛋白质，是目前蛋白质电化学研究的热点。本文为此具体探讨了蛋白质-纳米、蛋白质膜、蛋白质-双层类脂膜、蛋白质-DNA膜、蛋白质一表面活性剂与氧化还原蛋白质修饰电极的研究现状。     

Multivalent Ligands with Tailor-Made Anion Binding Motif as Stabilizers of Protein–Protein Interactions

Modulation of protein–protein interactions (PPIs) is essential for understanding and tuning biologically relevant processes. Although inhibitors for PPIs are widely used, the field still lacks the targeted design of stabilizers. Here, we report unnatural stabilizers based on the combination of multivalency effects and the artificial building block guanidiniocarbonylpyrrol (GCP), an arginine mimetic. Unlike other GCP-based ligands that modulate PPIs in different protein targets, only a tetrameric design shows potent activity as stabilizer of the 14-3-3ζ/C-Raf and 14-3-3ζ/Tau complexes in the low-micromolar range. This evidences the role of multivalency for achieving higher specificity in the modulation of PPIs.     

Inhibition of Amyloid Protein Aggregation Using Selected Peptidomimetics

Aberrant protein aggregation leads to the formation of amyloid fibrils. This phenomenon is linked to the development of more than 40 irremediable diseases such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and cancer. Plenty of research efforts have been given to understanding the underlying mechanism of protein aggregation, associated toxicity, and the development of amyloid inhibitors. Recently, the peptidomimetic approach has emerged as a potential tool to modulate several protein-protein interactions (PPIs). In this review, we discussed selected peptidomimetic-based approaches for the modulation of important amyloid proteins (Islet Amyloid Polypeptide, Amyloid Beta, α-synuclein, mutant p53, and insulin) aggregation. This approach holds a powerful platform for creating an essential stepping stone for the vital development of anti-amyloid therapeutic agents.     

Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2

Protein–protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.     

Discovery of Small-Molecule Modulators of Protein–RNA Interactions by Fluorescence Intensity-Based Binding Assay

Protein–RNA interactions mediate various cellular processes, the dysregulation of which has been associated with a list of diseases. Thus, novel experimental tools for monitoring protein–RNA interactions are highly desirable to identify new chemical modulators of these therapeutic targets. In this study, we constructed simple fluorescence intensity-based protein–RNA binding assays by testing multiple environment-sensitive organic fluorophores. We selected the oncogenic interaction between Lin28 and the let-7 microRNA and the important immunomodulatory Roquin–Tnf CDE interaction as representative targets. We adapted this assay to high-throughput screening for the identification of pyrazolyl thiazolidinedione-type molecules as potent small-molecule inhibitors of protein–microRNA interactions. We clearly showed the structure–activity relationships of this new class of Lin28–let-7 interaction inhibitors, and confirmed that cellular mature let-7 microRNAs and their target genes could be modulated upon treatment with the pyrazolyl thiazolidinedione-type inhibitor. We expect that our simple and adaptable screening approach can be applied for the development of various assay systems aimed at the identification of bioactive small molecules targeting protein–RNA interactions.     

Drugs targeting protein-protein interactions

Most biological processes involve permanent and nonpermanent interactions between different proteins, and many protein complexes play a key role in various human diseases. Therefore, molecules that prevent the formation of these protein complexes could be valuable new therapeutic agents to treat these diseases. Protein interfaces have not evolved to bind low-molecular-weight molecules, as is the case with enzyme catalytic sites. It is therefore difficult to identify small compounds that inhibit protein-protein interactions. However, there is considerable diversity in the structure of protein interfaces, some of which may be more attractive than others for medicinal chemistry. One of the main challenges in drug discovery is to identify these interfaces and to exploit their properties to make marketable drugs. Herein, the properties of protein interfaces are discussed in light of their use as drug targets.     

Oligomer Formation and Cross-Seeding: The New Frontier

The accumulation of protein aggregates in the brain is a defining feature of a number of neurodegenerative diseases. Though diseases vary in the composition of aggregated proteins (amyloid-β and tau are primarily implicated in Alzheimer's disease, α-synuclein is the primary protein aggregate in Parkinson's disease, etc.), similarities in the formation of soluble intermediate aggregates, some of which go on to deposit in stable fibrillar structures, suggests that the protein sequence may be far less important than the aggregate conformation to toxicity and onset of disease. Growing evidence suggests that intermediate or independently formed oligomeric aggregates are more highly toxic than fibrils, and are more efficient seeds for the aggregation of endogenous protein. Furthermore, the overlap of different aggregated proteins in disease, as well as the ability of amyloid oligomers to cross-seed the aggregation of each other, suggests that synergistic interactions between varying aggregant proteins is a critical component in neurodegeneration. The progression of aggregates along defined pathways throughout the brain is crucial to the spread of disease and likely depends upon the transport of aggregates from affected to unaffected brain regions. Thus, the presence of oligomeric seeds that more efficiently seed the aggregation of homologous and diverse proteins may underlie neurodegeneration.     

Tampering with Cell Division by Using Small‐Molecule Inhibitors of CDK–CKS Protein Interactions

Cyclin‐dependent kinases (CDKs) control many cellular processes and are considered important therapeutic targets. Large collections of inhibitors targeting CDK active sites have been discovered, but their use in chemical biology or drug development has been often hampered by their general lack of specificity. An alternative approach to develop more specific inhibitors is targeting protein interactions involving CDKs. CKS proteins interact with some CDKs and play important roles in cell division. We discovered two small‐molecule inhibitors of CDK–CKS interactions. They bind to CDK2, do not inhibit its enzymatic activity, inhibit the proliferation of tumor cell lines, induce an increase in G1 and/or S‐phase cell populations, and cause a decrease in CDK2, cyclin A, and p27^Kip1 levels. These molecules should help decipher the complex contributions of CDK–CKS complexes in the regulation of cell division, and they might present an interesting therapeutic potential.     

A Comprehensive Structural Overview of p38α Mitogen‐Activated Protein Kinase in Complex with ATP‐Site and Non‐ATP‐Site Binders

Herein we review all the currently available ATP‐site and non‐ATP‐site ligands bound to p38α mitogen‐activated protein kinase (MAPK) available in the RCSB Protein Data Bank (PDB). The co‐crystallized inhibitors have been classified into different families according to their experimental binding mode and chemical structure, and the ligand–protein interactions are discussed using the most representative compounds. This systematic structural analysis could provide some take‐home lessons for drug discovery programs aimed at the rational identification and optimization of new p38α MAPK inhibitors.     

动物蛋白胶共混改性研究

分别从凝胶强度、表观黏度和黏结强度分，探索了明胶、甘油、蔗糖、氯化钠共混对动物蛋白胶的性能影响。