类乳腺癌易感基因BRCA1肽的设计、合成及与抑癌基因蛋白RAD51肽段的相互作用

乳腺癌易感基因BRCA1肽对抑制女性乳腺癌病发有积极作用,其与乳腺癌细胞内抑癌基因蛋白RAD51相互作用的研究是乳腺癌药物发现的重要部分.通过Discovery Studio模拟类BRCA1肽与RAD51对接过程,利用R-DOCK评价系统从结果中筛选出4条评分较高的类BRCA1肽,采用固相逐步合成法制得.通过荧光光谱、圆二色光谱等方法研究了其与RAD51肽段(Pep158-180、Pep181-200、Pep241-260)的相互作用,发现4条类BRCA1肽的作用都强于BRCA1肽,这与模拟的结果相一致,其中BRCA1-3与RAD51的两个关键肽段(Pep158-180、Pep241-260)的相互作用明显强于BRCA1肽和其他类肽.该研究结果为乳腺癌药物分子设计提供了依据.     

基于ISC-SVR方法预测Th细胞表位

外源性抗原蛋白被抗原提呈细胞(APC)摄取送入溶酶体中被降解为长度不一的肽段. 在HLA-DM分子辅助下, MHC II类分子相关恒定链多肽(class II-associated invariant chain peptide, CLIP)从MHC II类分子的肽结合槽解离, 使得外源性抗原降解的肽段进入MHC II类分子空的肽结合槽中, 形成稳定的抗原肽-MHC II类分子复合物. 之后再被提呈到APC细胞表面供CD4⁺Th细胞的TCR识别, 激活Th细胞分泌细胞因子, 促进CTL细胞特异性杀伤靶细胞或辅助B细胞产生抗体. Th细胞的活化对机体的细胞免疫和体液免疫功能都有重要的辅助作用. 本工作基于迭代自洽策略与支持向量回归机(ISC-SVR)方法建立了MHC II类分子与外源性抗原肽结合亲合力预测模型, 采用13mer扩展核心结合序列可以提高预测模型的性能, 分别按照均值法、最大值法、结合法、加权平均值法4种方法计算MHC II类分子与抗原肽的结合亲合力值. 对17种MHC II类分子配型进行了回归分析, 与其他预测模型相比较, 本工作模型都得到了最佳AUC值. 最后, 以HLA DRB1*0101分子为例, 分析讨论了MHC II类分子与抗原肽的结合特异性.     

具有新型核心结构的肽类BACE1抑制剂的设计、合成及活性评价

以KMI-008为先导化合物,4-羟基或氨基取代的脯氨酸模拟其Pns,设计并合成了19条肽序列,用时间分辨荧光法测定目标肽体外对BACE1的抑制作用. 所合成化合物对BACE1有一定的抑制作用,其中两个化合物(LK-MX-41、LK-MX-42)与先导化合物活性相近,其核心结构由L-Phe-D-Pro组成,可以模拟BACE1的催化中心与底物相互作用的过渡态;含有该结构的肽序列,有可能成为研究肽类BACE1抑制剂的另一途径. 应用Autodock 4将所合成化合物与BACE1进行对接,结合体外活性测试结果对构效关系进行了初步探讨. 先导化合物及目标肽用固相法合成,经RP-HPLC测定纯度、ESI-MS确定相对分子量.     

新型含硫肿瘤坏死因子类肽抑制剂的合成与活性

为了发展新型TNF类肽抑制剂, 考虑到酶活性中心含有Zn²⁺离子, 我们以通式1的骨架为基础, 设计并合成了一类含有硫原子的类肽化合物2, 其具有三肽的基本骨架, 羟胺的游离羟基和侧链上的硫原子均可与金属蛋白酶活性中心的Zn²⁺络合, 起抑制活性作用.     

肽类树状大分子的合成及其在药物传输系统中的应用

树状大分子是近年来蓬勃发展的一类新型高分子材料, 其表面存在大量的官能团, 分子内部存在空腔且分子尺寸可控, 因此, 树状大分子已被广泛应用于众多的领域. 肽类树状大分子是指在树状大分子结构中含有肽键的一类大分子, 因其具有类似蛋白质一样的球状结构, 且具有优异的水溶性、生物相容性、生物降解性和细胞低毒性等特点, 所以, 肽类树状大分子可以作为药物传输的载体. 此外, 肽类树状大分子的疏水空腔可以装载疏水性药物, 对其起到增溶和缓释作用. 综述了肽类树状大分子的合成方法, 并对其与药物分子的结合机制及其在药物传输系统中的应用进行了总结与展望.     

抗原肽与MHC分子相互作用QM/MM分子动力学模拟研究

在MHC I类(major histocompatibility complex class I)分子抗原加工提呈过程中抗原蛋白在抗原提呈细胞(antigen-presenting cells, APC)的胞浆中被蛋白酶体(proteasome)裂解成短肽peptide, 由转运相关蛋白(transporter associated with antigen processing, TAP)将蛋白酶体裂解产生的短肽片段从胞浆转运至内质网腔. 短肽peptide在内质网中与新生成的MHC I类分子结合, 形成peptide-MHC复合体被提呈到APC细胞表面, 与T细胞表面抗原受体(T cell receptor, TCR)特异性识别结合, 使得CTL细胞开始活化、增殖、分化, 进而对肿瘤细胞进行特异性杀伤. 目前对CTL细胞如何识别抗原肽-MHC复合物分子及抗原短肽peptide如何与主要组织相容性复合体MHC分子的相互作用识别结合的机理还不是很清楚. 传统的预测CTL细胞表位的方法没有考虑受体与配体结合过程中电子结构的变化, 电子结构的变化需要用量子力学方法来处理. 本文采用QM/MM多尺度生物大分子的分子动力学模拟方法, 以天然抗原肽TAX (LLFGYPVYVYU)与HLA-A*0201分子结合的晶体结构为模板, 替换抗原肽“锚点”氨基酸, 将口袋氨基酸残基的原子极化电荷在空间形成的静电势用电多极矩分量表示. 用箱线图分析每个口袋氨基酸分子静电势变化和功能, 确定Pocket B的Glu63和Lys66的功能是精细识别氨基酸和一级结合氨基酸, Pocket F的Asp77, Tyr84的功能是精细识别氨基酸, 而Asp77, Lys146是一级结合氨基酸, 表明QM/MM方法在提取抗原肽与MHC I类分子识别结合特异性信息是可行的, 这对了解免疫识别机理和指导肿瘤疫苗的开发都具有指导意义.     

二茂铁类环肽的合成与分子识别研究

设计并合成了两个系列含二茂铁单元的1+1型和2+2型类环肽,用循环伏安法研究了1+1型二茂铁类环肽与含氧负离子和卤素负离子的包合作用.结果表明,类环肽能很好地识别这些常见的负离子.¹HNMR研究发现,类环肽对负离子的识别作用主要是通过类环肽酰胺键中氢与客体负离子形成分子间氢键实现的.     

电喷雾电离质谱法研究环肽对HIV-1调控区DNA的识别及其相关碎裂机理和稳定性

利用电喷雾电离质谱(ESI-MS)和二级质谱(MS/MS)研究了六种结构不同的环五肽, 环七肽以及环十肽与HIV-1调控区DNA的非共价键相互作用. 在研究中比较了不同识别分子与靶序列DNA结合的强弱, 发现环七肽CP5对靶点DNA具有高亲合性的结合. 用MS/MS法研究了环肽与DNA复合物的碎裂机理; 用升温实验研究了其热稳定性, 发现与CP5结合后能提高HIV-1双螺旋DNA的热稳定性.     

新型脱氢松香基苯并咪唑类衍生物的合成及其氯离子识别性能

以脱氢松香酸甲酯为原料, 经溴代、双硝化、还原、关环等步骤合成了五个新型脱氢松香基苯并咪唑类衍生物(6a～6e). 其结构用1H NMR和13C NMR进行了确证. 对6a～6e进行了阴离子识别研究, 并对其结构与氯离子识别能力的关系进行了讨论.     

聚类肽高分子材料及其结构与性能的研究

聚类肽又称为氮取代聚甘氨酸(N-聚甘氨酸),是一类具有优良生物相容性以及生物活性的可降解高分子材料.由于酰胺键的活泼氢被取代,聚类肽主链结构中消除了聚肽固有的多重氢键相互作用,其主链柔性较好,聚合物性质主要由侧链基团的种类及其物理化学性质决定.基于这种链结构特征,可以通过设计不同的侧基结构,有效地调节聚类肽高分子的热力学性能、降解性能和自组装行为等物理化学性质.合成聚类肽的方法主要有2种——开环聚合和固相合成.本文主要介绍了聚类肽高分子的本体与溶液自组装行为,系统阐明了如何通过调控聚类肽高分子的侧链结构,研究链结构与自组装行为之间的相互关系,进一步构筑具有独特相分离行为以及自组装结构的新型生物高分子,同时探讨了这些材料在生物医用和能源等领域的潜在应用.     

Influence of terminal substituents on the halide anion binding of foldamer-based receptors

Foldamers 1–4 incorporating different terminal substituents have been designed and synthesized for binding halide anions.~1H NMR titration experiments carried out in DMSO-d_6/CDCl_3(15/85, v/v)demonstrated that the short oligo (aryltriazole)s backbone 1 could not bind halide anions unless that amide H-bond donors were incorporated at the termini of the oligomer. Terminal substituents on oligo(aryltriazoleamide)s foldamers 2–4 display a considerable influence on the binding affinities of the foldamers for halide anions. Large steric hindrance of the terminal substituents was found to be unfavorable for binding halide anions, but aromatic π-π interactions between two terminal substituents are capable of stabilizing the conformation of foldamers thus giving rise to an enhancement in the binding strengths. However, the terminal substituents were found to hardly affect the binding selectivity in the studied cases.     

Anion complexation by calix[3]thieno[1]pyrrole: the medium effect

The interaction of calix[3]thieno[1]pyrrole, 1, and halide and dihydrogen phosphate anions in a variety of solvents (acetonitrile, propylene carbonate, N,N-dimethylformamide, and dimethyl sulfoxide) has been investigated through 1H NMR, conductance measurements, and titration calorimetry. 1H NMR measurements reveal the sites of interaction of the ligand with the anions in CD3CN while the composition of the complex was determined through conductance measurements. A quantitative assessment of anion-ligand interactions is provided. Thus the thermodynamics of complexation of 1 with halide and dihydrogen phosphate anions in dipolar aprotic media at 298.15 K is reported. These data are interpreted in terms of the thermodynamics of transfer of reactants and product from a reference solvent (acetonitrile) to other solvents. The crucial role played by the solvent on the ability of the ligand to interact with anions and on the composition of the complex is demonstrated.     

Strong halogen bonding of 1,2-diiodoperfluoroethane and 1,6-diiodoperfluorohexane with halide anions revealed by UV-Vis, FT-IR, NMR spectroscopes and crystallography

The spectroscopic methods UV-Vis absorption, FT-IR and (13)C and (19)F NMR demonstrate that 1,2-diiodoperfluoroethane (DIPFE) and 1,6-diiodoperfluorohexane (DIPFH) display strong halogen bonding with halide anions. A 1?:?1 stoichiometry of DIPFE or DIPFH with halide anion is confirmed, and the bonding constants and molar extinction coefficients are obtained. With the same halide, DIPFH possesses greater bonding constants and molar extinction coefficients than DIPFE. Furthermore, the bonding constants present in this article are far greater than those of all halogen bonding complexes reported. Interestingly, the FT-IR spectrum indicates that halogen bonding promotes a conversion from gauche to trans conformer of DIPFE. The X-ray data further confirm a 1?:?1 stoichiometry and all DIPFE and DIPFH exist in trans conformers in cocrystals which were assembled with halide anions. As potential persistent organic pollutions, iodinated perfluoroalkanes have been paid much attention. The present study will benefit current research of their separation and recognition in environmental samples.     

Spectroscopic, structural, and theoretical studies of halide complexes with a urea-based tripodal receptor

A urea-based tripodal receptor L substituted with p-cyanophenyl groups has been studied for halide anions using (1)H NMR spectroscopy, density functional theory (DFT) calculations, and X-ray crystallography. The (1)H NMR titration studies suggest that the receptor forms a 1:1 complex with an anion, showing a binding trend in the order of fluoride > chloride > bromide > iodide. The interaction of a fluoride anion with the receptor was further confirmed by 2D NOESY and (19)F NMR spectroscopy in DMSO-d(6). DFT calculations indicate that the internal halide anion is held by six NH···X interactions with L, showing the highest binding energy for the fluoride complex. Structural characterization of the chloride, bromide, and silicon hexafluoride complexes of [LH(+)] reveals that the anion is externally located via hydrogen bonding interactions. For the bromide or chloride complex, two anions are bridged with two receptors to form a centrosymmetric dimer, while for the silicon hexafluoride complex, the anion is located within a cage formed by six ligands and two water molecules.     

The synthesis and recognition properties of colorimetric fluoride receptors bearing sulfonamide

Two artificial receptors, 1,2-bis-p-substituted phenyl-sulfonamido-4,5-bis-nitrobenzene, have been designed and synthesized. The interactions of these receptors with halide anions are determined by UV-vis and ¹H NMR titration experiments. Results indicate that two receptors have strong sensitivity and selectivity for fluoride among halide anions. In addition, the visible color changes upon the addition of fluoride anion can make the receptors as convenient detection tools for fluoride anion.     

Sulfonamide carbazole receptors for anion recognition

Carbazole-based receptors functionalized with two sulfonamide groups have been synthesized and their properties as anion receptors have been evaluated. The receptor with bis(trifluoromethyl)aniline groups has shown a very high affinity for halide ions, especially remarkable as only two hydrogen bonds are formed in the complexes. (1)H NMR and fluorescence titrations have been carried out and binding constants up to 7.9 × 10(6) M(-1) have been reached. X-ray structures have been obtained and a modelling study has shown the possible reasons for the large affinity of these compounds for halide anions.     

四(对己氧苯基)卟啉稀土配合物的合成,表征和电化学性质

合成了四种乙酰丙酮-meso-四(对己氧苯基)卟啉稀土配合物,LnT(p-C6H13O)PPacac(Ln:Y,Dy,Er,Yb;Hacac:乙酰丙酮),研究了其紫外-可见光谱、红外光谱、氢核磁共振谱和荧光光谱,对各个谱带进行了归属,并用循环伏安法对其电化学性质进行了研究.     

Macrocycles containing tin. A small,exclusive host for the fluoride ion

The binding properties of macrobicyclic host 1 in solution were studied by NMR spectroscopy; host 1 maintains structural integrity in the presence of halide anions and binds fluoride ion strongly while it excludes all other halides.     

Tetrakis(imidazolium) macrocyclic receptors for anion binding

New (tetrakis)imidazolium macrocyclic receptor systems of variable cavity size have been synthesised by stepwise alkylation reactions of bis(imidazolium) precursor compounds. Proton NMR titration studies reveal the macrocycles to strongly bind halide and benzoate anions, with two receptor systems displaying notable selectivity for fluoride in competitive acetonitrile-water (9:1) solvent media.     

A ‘clicked’ macrocyclic probe incorporating Binol as the signalling unit for the chiroptical sensing of anions

We describe a macrocyclic chiroptical sensor for the detection of halide anions, with the Binol moiety acting as the CD signalling unit. The macrocycle is conveniently synthesized using CuAAC ‘click’ reactions in the cyclization step; this methodology installs 1,2,3-triazole moieties within the macrocyclic backbone, able to directionally bind anions by means of CH?X^– hydrogen bonds. ¹H NMR complexation studies in CDCl₃ reveal weak binding to halide and aliphatic carboxylate anions. Halide anions, however, when held into the macrocyclic cavity, are able to trigger a large chiroptical response originating from the steric interaction with the Binol moiety, which changes its dihedral angle, thus modulating its characteristic CD signature.