Survivin小分子抑制剂的研究进展

Survivin是凋亡抑制蛋白家族的一员,在抑制细胞凋亡、调控细胞周期、参与血管形成等方面发挥重要的生物学功能。Survivin在多种肿瘤组织中过量表达,与肿瘤不良预后和耐药性密切相关。Survivin作为一种潜在的肿瘤治疗靶点,其小分子抑制剂用于肿瘤治疗的研究为人们所关注。概述了Survivin的结构、功能及其在肿瘤组织中的特异性表达,综述了目前靶向Survivin的小分子抑制剂的研究进展。     

综述与专论：蛋白质错误折叠相关疾病的多肽药物研究进展

蛋白质和多肽发生错误折叠形成不可溶的淀粉样纤维的过程,与阿尔茨海默病、帕金森病等多种神经退行性疾病密切相关。这些疾病可导致认知能力下降以及运动缺陷等症状。虽然已有多种相关治疗方案处于临床试验中,但目前仍无明确有效的方法可治愈或长期减缓疾病的进展。探寻和研究抑制淀粉样聚集、识别并促进毒性聚集物清除的抑制剂分子是药物研发的重要策略之一。在不同类型的抑制剂中,多肽类抑制剂因具有高特异性、低毒性、多样性,以及修饰后的抗水解稳定性和血脑屏障通透性,有望成为候选药物分子。本文总结了针对阿尔茨海默病相关的Aβ和Tau蛋白以及帕金森病相关的α-synuclein蛋白淀粉样纤维化的多肽抑制剂研究进展。基于淀粉样纤维化核心序列及纤维核心结构进行合理设计,或通过随机筛选,均可获得多肽抑制剂。这些天然和非天然的多肽分子大多具有抑制淀粉样纤维化、解聚成熟纤维和降低细胞毒性的作用,其中一些多肽在退行性疾病动物模型实验中,显示出降低脑损伤和缓解认知及运动障碍的效果。这些研究揭示了多肽作为蛋白质错误折叠和聚集相关疾病药物的特点,为研发一类新的有效药物奠定了基础。     

蛋白质错误折叠相关疾病的多肽药物研究进展

蛋白质和多肽发生错误折叠形成不可溶的淀粉样纤维的过程,与阿尔茨海默病、帕金森病等多种神经退行性疾病密切相关。这些疾病可导致认知能力下降以及运动缺陷等症状。虽然已有多种相关治疗方案处于临床试验中,但目前仍无明确有效的方法可治愈或长期减缓疾病的进展。探寻和研究抑制淀粉样聚集、识别并促进毒性聚集物清除的抑制剂分子是药物研发的重要策略之一。在不同类型的抑制剂中,多肽类抑制剂因具有高特异性、低毒性、多样性,以及修饰后的抗水解稳定性和血脑屏障通透性,有望成为候选药物分子。本文总结了针对阿尔茨海默病相关的Aβ和Tau蛋白以及帕金森病相关的α-synuclein蛋白淀粉样纤维化的多肽抑制剂研究进展。基于淀粉样纤维化核心序列及纤维核心结构进行合理设计,或通过随机筛选,均可获得多肽抑制剂。这些天然和非天然的多肽分子大多具有抑制淀粉样纤维化、解聚成熟纤维和降低细胞毒性的作用,其中一些多肽在退行性疾病动物模型实验中,显示出降低脑损伤和缓解认知及运动障碍的效果。这些研究揭示了多肽作为蛋白质错误折叠和聚集相关疾病药物的特点,为研发一类新的有效药物奠定了基础。     

BAG3的结构和功能的研究进展

Bcl2相关永生基因3(BAG3)被鉴定为抗凋亡和前自噬因子,包含BAG、WW和PXXP三个结构域。BAG3与多种蛋白相互作用,被多种信号激活,又能激活多种信号通路,调控多种生理和病理过程,提示开发其特异性抑制剂可能为肿瘤的化学治疗提供候选药物,而开发其特异性激活剂可能为肌肉及神经退行性疾病的防治提供候选药物。现对人源BAG3的结构特征、相互作用蛋白、信号通路及生物学功能进行综述。     

乙酰肝素酶的生物学特性的研究进展

乙酰肝素酶是切割哺乳动物细胞中硫酸肝素蛋白多糖侧链——硫酸乙酰肝素的内源性糖苷酶,是抗肿瘤转移的理想靶点。本就乙酰肝素酶的分子结构特点、亚细胞定位、活性调控机制、与肿瘤转移的关系、底物特异性和抑制剂开发等方面的研究进展进行了综述。     

噬菌体展示技术及其在肿瘤研究中的应用

噬菌体表面展示技术是一项特异性多肽或蛋白的筛选技术,它将随机序列的多肽或蛋白片段与噬菌体衣壳蛋白融合表达而呈现于病毒表面,被展示的多肽能保持相对独立的空间结构,使其能够与配体作用而达到模仿性筛选特异性分子表位,从而提供了高通量高效率的筛选系统。近年来噬菌体展示技术已广泛应用于肿瘤抗原抗体库的建立、单克隆抗体制备、多肽筛选、疫苗研制、肿瘤相关抗原筛选和抗原表位研究、药物设计、癌症检测和诊断、基因治疗及细胞信号转导研究等。就近年来噬菌体展示技术在肿瘤相关研究中的运用作以综述。     

泛素特异性蛋白酶14的研究进展

泛素特异性蛋白酶14(ubiquitin-specific protease 14,USP14)是真核生物体内普遍存在的一种去泛素化酶,在编辑泛素链长度以及维持游离泛素库的稳定中发挥重要作用。它既可通过去泛素化调控靶蛋白的降解,又可通过多种信号通路参与肿瘤以及神经系统疾病的发生发展,因此USP14有望成为相关疾病治疗的极具潜力的新靶点。文章将从结构、功能、底物蛋白、信号通路、相关疾病以及抑制剂等方面对USP14的研究进展做一综述。     

基于核酸适配体的生物分析新方法研究进展

核酸适配体是从随机文库中采用SELEX技术筛选所得的单链短链寡核苷酸片段(通常为15-80个ss DNA或ss RNA)。其能够折叠形成独特稳定的三维结构,通过静电相互作用,氢键,范德华力,碱堆叠或多种作用力组合特异性地与多种靶标结合。适配体因具有构象变化能力而被用作生物分析中的理想识别配体。目前,基于适配体的生物分析新方法得到广泛研究,并用于蛋白多肽类药物分析、疾病标志物诊断、外泌体检测、循环肿瘤细胞检测和病毒检测等方面。本文综述了核酸适配体用于生物分析方法开发的最新进展,比较和讨论不同分析方法,并对基于适配体的生物分析新方法提出了设想和展望,为开发新的生物分析方法和检测技术提供了思路和借鉴。     

成纤维细胞激活蛋白α与肿瘤发展进程的研究

肿瘤微环境对肿瘤的发生、发展具有重要的意义。选择性表达于肿瘤微环境重要组成部分——肿瘤相关成纤维细胞（carcinoma associated fibroblasts,CAFs）表面的成纤维细胞激活蛋白α（fibroblast activation protein-α,FAPα）广泛参与了肿瘤的生长、侵袭、转移以及肿瘤细胞外基质重建、血管生成、免疫逃逸等过程,从而促进了肿瘤的发展进程。FAPα具有蛋白水解酶活性,并作用于细胞信号通路,但FAPα在肿瘤微环境中发挥功能的具体分子机制还有待进一步研究。由于FAPα的表达具有肿瘤组织特异性,因此,以FAPα作为肿瘤基质标志物,对肿瘤进行病理诊断和免疫治疗将成为新兴的研究靶点。对FAPα的主要生物学性状进行概述,并综述了其对肿瘤细胞的生长、侵袭、转移以及肿瘤细胞外基质重建、血管生成、免疫逃逸等方面的重要影响。     

microRNA化学小分子抑制剂的研究进展

药物靶点的研究一直是新药研发中最重要的内容之一,microRNA(miRNA)作为调节基因与蛋白之间相互关系的纽带无疑是药物靶点研究的重要对象,以它们作为靶点的药物设计和药物研发工作也在不断深入,并获得了一系列新发现.其中,对细胞内miRNA的表达或者功能具有调控活性的化学小分子的研究很值得关注.这些化学小分子不但可以用于研究细胞内miRNA的调控网络,而且基于其对重大疾病,如肿瘤、心脏疾病、神经性疾病等相关的miRNA的调控,可能在将来的疾病治疗方面有着潜在的重要作用.本文围绕miRNA化学小分子抑制剂及其筛选方法进行综述,通过总结归纳现有的研究进展,希望对今后的miRNA特异性小分子抑制剂的发现和研究提供借鉴.     

Molecular recognition of fibroblast activation protein for diagnostic and therapeutic applications

Fibroblast activation protein (FAP) is a non-classical serine protease expressed predominantly in conditions accompanied by tissue remodeling, particularly cancer. Due to its plasma membrane localization, FAP represents a promising molecular target for tumor imaging and treatment. The unique enzymatic activity of FAP facilitates development of diagnostic and therapeutic tools based on molecular recognition of FAP by substrates and small-molecule inhibitors, in addition to conventional antibody-based strategies.In this review, we provide background on the pathophysiological role of FAP and discuss its potential for diagnostic and therapeutic applications. Furthermore, we present a detailed analysis of the structural patterns crucial for substrate and inhibitor recognition by the FAP active site and determinants of selectivity over the related proteases dipeptidyl peptidase IV and prolyl endopeptidase. We also review published data on targeting of the tumor microenvironment with FAP antibodies, FAP-targeted prodrugs, activity-based probes and small-molecule inhibitors. We describe use of a recently developed, selective FAP inhibitor with low-nanomolar potency in inhibitor-based targeting strategies including synthetic antibody mimetics based on hydrophilic polymers and inhibitor conjugates for PET imaging.In conclusion, recent advances in understanding of the molecular structure and function of FAP have significantly contributed to the development of several tools with potential for translation into clinical practice.     

Cleavage-site specificity of prolyl endopeptidase FAP investigated with a full-length protein substrate

Fibroblast activation protein (FAP) is a prolyl-cleaving endopeptidase proposed as an anti-cancer drug target. It is necessary to define its cleavage-site specificity to facilitate the identification of its in vivo substrates and to understand its biological functions. We found that the previously identified substrate of FAP, α(2)-anti-plasmin, is not a robust substrate in vitro. Instead, an intracellular protein, SPRY2, is cleavable by FAP and more suitable for investigation of its substrate specificity in the context of the full-length globular protein. FAP prefers uncharged residues, including small or bulky hydrophobic amino acids, but not charged amino acids, especially acidic residue at P1', P3 and P4 sites. Molecular modelling analysis shows that the substrate-binding site of FAP is surrounded by multiple tyrosine residues and some negatively charged residues, which may exert least preference for substrates with acidic residues. This provides an explanation why FAP cannot cleave interleukins, which have a glutamate at either P4 or P2', despite their P3-P2-P1 sites being identical to SPRY2 or α-AP. Our study provided new information on FAP cleavage-site specificity, which differs from the data obtained by profiling with a peptide library or with the denatured protein, gelatin, as the substrate. Furthermore, our study suggests that negatively charged residues should be avoided when designing FAP inhibitors.     

淡水入侵生物沼蛤的污损机制与防污措施研究进展

沼蛤是一种典型的淡水入侵贝类,能够利用其分泌的足丝牢固黏附在多种水下基质表面,引起严重的生物污损问题。沼蛤污损不但影响水生态系统健康,也给水利工程、交通运输、水产养殖等行业带来经济损失,已成为全球水生态系统安全和国民经济重要行业的潜在威胁,相关防污工作亟待开展。欲从根本上解决沼蛤污损问题,一方面需要加强对其基础生物学特性和污损机制的深入解析,另一方面也需要在此基础上研发更加经济、高效、环境友好的防污措施。本文综述了近年来国内外关于沼蛤污损生物学特性、污损机制和防污措施方面的研究进展,尤其是对沼蛤生物污损发生的主要机制如足探测识别、足丝黏附和环境影响等方面进行了总结,也从物理、化学、生物和防污材料等角度阐述了现有的沼蛤污损控制措施并对未来发展方向进行了展望,以期更加深入地理解沼蛤生物污损现象,为揭示其作用机制、制定科学有效的防污措施、维护水生态系统安全提供数据支撑,综述内容对于水下仿生材料研发也具有重要的参考价值。     

Histone deacetylase 10, a potential epigenetic target for therapy

Histone deacetylase (HDAC) 10, a class II family, has been implicated in various tumors and non-tumor diseases, which makes the discovery of biological functions and novel inhibitors a fundamental endeavor. In cancers, HDAC10 plays crucial roles in regulating various cellular processes through its epigenetic functions or targeting some decisive molecular or signaling pathways. It also has potential clinical utility for targeting tumors and non-tumor diseases, such as renal cell carcinoma, prostate cancer, immunoglobulin A nephropathy (IgAN), intracerebral hemorrhage, human immunodeficiency virus (HIV) infection and schizophrenia. To date, relatively few studies have investigated HDAC10-specific inhibitors. Therefore, it is important to study the biological functions of HDAC10 for the future development of specific HDAC10 inhibitors. In this review, we analyzed the biological functions, mechanisms and inhibitors of HDAC10, which makes HDAC10 an appealing therapeutic target.     

Analysis of Coxiela burnetti dihydrofolate reductase via in silico docking with inhibitors and molecular dynamics simulation

Coxiella burnetii is a gram-negative bacterium able to infect several eukaryotic cells, mainly monocytes and macrophages. It is found widely in nature with ticks, birds, and mammals as major hosts. C. burnetii is also the biological warfare agent that causes Q fever, a disease that has no vaccine or proven chemotherapy available. Considering the current geopolitical context, this fact reinforces the need for discovering new treatments and molecular targets for drug design against C. burnetii. Among the main molecular targets against bacterial diseases reported, the enzyme dihydrofolate reductase (DHFR) has been investigated for several infectious diseases. In the present work, we applied molecular modeling techniques to evaluate the interactions of known DHFR inhibitors in the active sites of human and C. burnetii DHFR (HssDHFR and CbDHFR) in order to investigate their potential as selective inhibitors of CbDHFR. Results showed that most of the ligands studied compete for the binding site of the substrate more effectively than the reference drug trimethoprim. Also the most promising compounds were proposed as leads for the drug design of potential CbDHFR inhibitors.     

Role of microRNA-155 in autoimmunity

MicroRNAs (miRNAs) have recently emerged as a major class of gene expression regulators linked to most biological functions. MiR-155 is encoded within a region known as B cell integration cluster (Bic) gene, identified originally as a frequent integration site for the avian leukosis virus. Disregulation of endogenous miR-155 has been implicated in the pathogenesis of human cancers. Recently, aberrant expression of miR-155 was observed in many autoimmune conditions, including rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). Moreover, functional analysis demonstrated that miR-155 has powerful regulatory potential in a wide variety of immune cells through targeting specific mRNAs. Since pathogenic immune cells play a pivotal role in pathogenesis of human autoimmune diseases, miR-155 might be a versatile therapeutic target. This review will discuss the current understandings for the role of miR-155 in autoimmunity.     

Strategies for analysis of glycoprotein glycosylation

Glycoproteins are known to exhibit multiple biological functions. In order to assign distinct functional properties to defined structural features, detailed information on the respective carbohydrate moieties is required. Chemical and biochemical analyses, however, are often impeded by the small amounts of sample available and the vast structural heterogeneity of these glycans, thus necessitating highly sensitive and efficient methods for detection, separation and structural investigation. The aim of this article is to briefly review suitable strategies for characterization of glycosylation at the levels of intact proteins, glycopeptides and free oligosaccharides. Furthermore, methods commonly used for isolation, fractionation and carbohydrate structure analysis of liberated glycoprotein glycans are discussed in the context of potential applications in glycoproteomics.     

Current and prospective applications of non-proteinogenic amino acids in profiling of proteases substrate specificity

Abstract Proteases recognize their endogenous substrates based largely on a sequence of proteinogenic amino acids that surrounds the cleavage site. Currently, several methods are available to determine protease substrate specificity based on approaches employing proteinogenic amino acids. The knowledge about the specificity of proteases can be significantly extended by application of structurally diverse families of non-proteinogenic amino acids. From a chemical point of view, this information may be used to design specific substrates, inhibitors, or activity-based probes, while biological functions of proteases, such as posttranslational modifications can also be investigated. In this review, we discuss current and prospective technologies for application of non-proteinogenic amino acids in protease substrate specificity profiling.     

A cell-based fluorescent assay for FAP inhibitor discovery

To facilitate the discovery of FAP inhibitors, a convenient cell-based fluorescent assay was developed by using a commonly available U87MG cell line and a FAP-specific substrate Suc-Gly-Pro-AMC. The assay enabled the fast determination of multiple IC₅₀s by simply incubating a solution of phosphate-buffered saline in a 96-well plate within 30 min. The substrate specificity, cross-reaction and other related conditions were systematically optimized. This method was successfully applied to determine the IC₅₀s of seven known inhibitors. The results are in consistence with the trend reported, which indicating that this practical assay is a valuable method to accelerate the discovery of FAP inhibitor.     

K6非典型泛素化修饰研究进展

泛素化是一种存在于真核生物内的蛋白质翻译后修饰,介导了蛋白质的特异性降解与信号转导,参与了诸多生命过程的调控进而影响着机体方方面面的功能。泛素化网络的紊乱和失衡是导致人类严重疾病的重要原因。泛素分子可以形成8种不同拓扑结构的同质泛素链,其丰度和功能差别巨大。目前,丰度较高的K48及K63经典泛素链的修饰底物较多、功能研究相对充分,而其他非典型泛素链的含量低、研究相对较少,但是诸多证据表明非典型泛素链在细胞内发挥着重要的调节功能。K6泛素链是一种重要的非典型泛素链,与K48链相似,具有紧密的空间结构。目前研究发现K6泛素链在DNA损伤修复、线粒体质量控制等过程中发挥重要调节功能,在肿瘤发生、发展以及帕金森疾病的致病过程中有着重要的作用。目前,由于缺乏特异性的K6泛素链抗体和有效的富集手段,导致K6泛素链修饰的底物、调控机制研究相对较少,诸多调控过程和功能有待进一步深入研究。本文系统综述了K6非典型泛素链的结构特征、调控机制以及相关的生物学功能与疾病,为K6泛素链的功能研究提供参考。