培养化学生物学复合型本科生的探索

1　培养化学生物学复合型人才的时代背景　　生命体系是目前化学研究最重要的对象之一。几年前 ,我国就已有学者提出 ,分子以上层次的化学是研究化学、生物学复杂系统的一部分 ,它将会在从生物医学到化学之间的辽阔领域展现出新的活力[1] ,并预测可能会产生一门被称为化学生物学的交叉学科[2 ] 。最近 ,吴厚铭先生通过对当今各国学科现状与文献的分析 ,认为化学生物学这一重要的新兴交叉学科已经形成[3 ] 。该学科适应化学与生物学和医学等学科领域相互交叉、相互渗透的趋势 ,采用生物学家不熟悉的化学手段 ,如运用小分子或人工设计合成的分…     

我国化学生物学研究新进展

作为化学领域的一门新兴二级学科,化学生物学已经成为具有举足轻重作用的交叉研究领域,是推动未来生命和化学学科发展的重要动力。近年来,我国的化学生物学研究正在以前所未有的速度蓬勃发展,在基础建设、人才培养、研究经费支持等方面都有了长足的进步。尤其是以国家自然科学基金委"基于化学小分子探针的信号转导过程研究"重大研究计划为依托,我国的化学生物学工作者以小分子探针为工具,充分发挥化学与生命科学等多学科综合交叉的优势,对细胞信号转导中的重要分子事件和机理进行了深入的探索,在一些前沿方向上取得了突出的成绩,相关研究结果多次发表在顶级的国际期刊上。本文对近两年来我国化学生物学领域取得的突出进展加以归纳和介绍:(1)基于小分子化合物及探针的研究。利用有机化学手段,通过设计合成一系列多样化的小分子化合物,以这些探针为工具深入开展了细胞生理、病理活动的调控机制、细胞关键信号转导通路及重要靶标、抑制剂和标记物的发现、基于金属催化剂的活细胞生物分子激活等方面的研究;(2)以化学生物学技术为手段,着重发展了针对蛋白质、核酸和糖等生物大分子的合成、特异标记与操纵方法,用以揭示这些生物大分子所参与的生命活动的调控机制;(3)采用信号传导过程研究与靶标发现相结合,以实现"从功能基因到药物"的药物研发模式,发展了药物靶标功能确证与化合物筛选的联合研究策略;(4)以化学分析为手段,发展了在分子水平、细胞水平或活体动物水平上,获取生物学信息的新方法和新技术。这些研究成果极大地推动了我国化学生物学的进步。共引用63篇参考文献。     

生物模拟转氨反应在蛋白质修饰中的应用

作为化学生物学研究的重要方向,生物正交反应的发展与应用为生命科学研究提供了有力武器.利用生物正交反应,人们可以将合成分子与目标天然大分子在特定位点上实现特异性连接,进而达成诸如标记、定位、功能化、固定等一系列目标.生物模拟转氨反应及其衍生反应是一类特异性蛋白质N端修饰的生物正交反应,与天然蛋白侧链、C端的连接反应相互补充.由于该反应具有高效性、通用性、温和性及不需要引入突变或非天然氨基酸等优点,从发现以来已较为广泛地运用于蛋白质化学生物学的多个相关领域.在介绍其基本原理及反应优化的基础上,综述该类反应的发展及应用情况.     

基于核酸物理有机化学原理探讨化学致癌相关问题的分子机制

核酸（DNA,RNA）作为遗传信息的载体是生物体内最重要的生物大分子之一。作为有机分子,其功能必然基于其本身结构和化学性质。从核苷酸与寡聚核苷酸的化学反应性质入手阐述3类主要的与DNA的反应,即与静态DNA反应导致结构变化;与动态过程中的DNA反应导致功能受阻;碱基插入型导致突变。详细分析了各类与DNA作用分子的物理化学机制,并讨论其与化学致癌、癌症化疗、化学诱变等在分子层面的联系。希望对核酸相关的化学、生物学及医学的教学与研究有所帮助。     

2002年欧洲出版的分析化学新刊介绍

1　《芯片上的实验室》(Ｌａｂｏｎａｃｈｉｐ)《芯片上的实验室》由联合王国皇家化学会出版。 2 0 0 1年试刊两期 ,2 0 0 2年正式出版季刊。内容涉及合成化学、生物工艺、电子学、分析化学、环境监测、药物筛选、医学诊断、临床化学、药物材料科学、工程学、流体学、研究废物最少化、反应器工艺和制作、机器人学、组合化学、基因组学、蛋白组学、细胞组学等。重点报道有机合成和生物学合成、生物 免疫分析、聚合物微制作、生物学矩阵微型加工、催化(生物学 )、脱氧核糖核酸测序和分子诊断学、微型化学反应器件和工艺、聚合酶链式反应、微型…     

纳米尺度和单分子水平上的化学生物学研究

化学生物学是化学与生命科学交叉融合的新兴学科。在纳米尺度和单分子水平上原位、活体、实时研究化学生物信息是化学生物学的重要研究方向。分析化学工作者利用纳米技术和分子生物学的最新研究成果 ,在这一研究方向取得了重要进展 ,为化学生物学的发展做出了积极贡献。本文重点介绍实验室利用生物亲和性核壳纳米颗粒和分子信标核酸探针所发展的一系列原位、活体、实时检测、分离生命体内痕量活性物质的新原理、新技术及其在化学生物学研究中的应用。     

生物界面上的化学过程——关于化学生物学研究前沿的讨论

在细胞和固体表面建立的生物界面上发生的化学-生物学过程是一个医学、环境、农业和生物技术共同面对的问题.以破骨细胞介导的骨再吸收过程为例阐述过程中的生物事件顺序,提出有待解决的化学问题.     

化学生物学中识别与组装的若干问题

化学与生物学的交叉与融合产生了新学科——化学生物学，开拓了化学和生物学研究的新领域，使人类得以从分子水平来阐释生命过程，揭示生命的奥秘。分子识别和组装是体系的构筑与功能集成的基础，也是自然界生物进行信息存贮、复制和传递的基础，以此来研究构筑具有特定生物学功能的超分子体系，对揭示生命现象和过程具有重要意义。本文结合我们的研究工作从（1）谷胱甘肽过氧化物酶(GPX)模拟与底物识别；（2）医用再生材料与活性支架；（3）类病毒颗粒的组装与解组装3个方面讨论了化学生物学中的识别与组装的意义。     

医用基础化学教材改革的几点思考

化学是医学、药学和生物学的重要基础。特别是近年来分子生物学(molecularbiology)、分子医学(molecularmedicine),遗传组学(genomics)、蛋白组学(proteomics)、代谢组学(metabonomics)等学科的相继出现,标志着生命科学的发展进入了分子水平,化学在生命科学中的重要性更加突出。如何不失时机地将化学学科作为一个基础学科整体介绍给医学、药学和生物学的学生,又在教学中将化学与医学、药学和生物学的紧密联系介绍给学生,从而构建出一套对医学、药学和生物学学生适用的生物医药类专业化学基础课体系,并在此基础上,搭建为生物医药类专业学生服…     

化学遗传学和多样性合成

多样性合成是化学合成思维上的一个突破 ,是化学生物学、组合化学、新药研究相互交叉、相互渗透的产物。多样性合成运用正向合成分析 ,通过选择合适的构建模块、立体化学控制因素和分支反应路径 ,灵活运用产生结构复杂性的反应和构象分析策略 ,构建结构复杂多样的化合物库。多样性合成与化学遗传学的结合使得系统地利用小分子解决生物学课题成为可能     

从生物有机化学到化学生物学

生物体系中的发现一直是与小分子连系在一起的.生物有机化学是生物学和有机化学相互交叉发展起来的新领域,特别是小分子与蛋白结合后引起蛋白功能变化的研究如抑制作用和活化.化学生物学和结构多样性有机合成使系统研究生物学成为可能,人工转录因子可以用作探针来发现生命过程中新的奥秘.     

Lipidated ras and rab peptides and proteins--synthesis, structure, and function

Chemical biology can be defined as the study of biological phenomena from a chemical approach. Based on the analysis of relevant biological phenomena and their structural foundation, unsolved problems are identified and tackled through a combination of chemistry and biology. Thus, new synthetic methods and strategies are developed and employed for the construction of compounds that are used to investigate biological procedures. Solid-phase synthesis has emerged as the preferred method for the synthesis of lipidated peptides, which can be chemoselectively ligated to proteins of the Ras superfamily. The generated peptides and proteins have solved biological questions in the field of the Ras-superfamily GTPases that are not amendable to chemical or biological techniques alone.     

Molecular Photochemistry: Recent Developments in Theory

Photochemistry is a fascinating branch of chemistry that is concerned with molecules and light. However, the importance of simulating light‐induced processes is reflected also in fields as diverse as biology, material science, and medicine. This Minireview highlights recent progress achieved in theoretical chemistry to calculate electronically excited states of molecules and simulate their photoinduced dynamics, with the aim of reaching experimental accuracy. We focus on emergent methods and give selected examples that illustrate the progress in recent years towards predicting complex electronic structures with strong correlation, calculations on large molecules, describing multichromophoric systems, and simulating non‐adiabatic molecular dynamics over long time scales, for molecules in the gas phase or in complex biological environments.     

Artificial enzyme catalysis controlled and driven by light

Bio-inspired chemistry based on photoresponsive molecules is a rapidly developing new strategy to mimic the function of various biological systems. The interaction of electromagnetic radiation with molecular systems is ideally suited for the control and powering of dynamic processes at the speed of light. Besides typical applications in artificial photosynthesis, many other aspects, such as the catalytic turnover of substrates or the controlled release or uptake of small bioactive molecules, are readily verified with light-driven model systems. The potential of this novel approach in biomimetic chemistry is briefly explored in this concept article.     

化学生物学在生物芯片技术中的角色

化学生物学是一个新兴的化学与生物学的交叉学科.它的基本任务是揭示生命运动的化学本质,发展生命调控的化学方法,提供生命研究的化学技术.本文以化学生物学在生物芯片技术发展中扮演的角色为例讨论当前化学生物学发展的特点.     

Natural Products as Probes of Cellular Function: Studies of Immunophilins

One of the great mysteries of cell biology remains the mechanism of information transfer, or signaling, through the cytoplasm of the cell. Natural products that inhibit this process offer a unique window into fundamental aspects of cytoplasmic signal transduction, the means by which extracellular molecules influence intracellular events. Thus, natural products chemistry, including organic synthesis, conformational analysis, and methods of structure elucidation, is a powerful tool in the study of cell function. This article traces our understanding of a group of natural products from the finding that they inhibit cytoplasmic signaling to their current recognition as mediators of the interaction between widely distributed protein targets. The emphasis of the discussion is primarily structural. The interactions between the natural-product ligands and their protein receptors are analyzed at a molecular level in order to shed light on the molecular mechanisms of the biological functions of these compounds. In the process we hope to illustrate the power of chemical analysis as applied to biological systems. Through chemistry we can understand the molecular basis of biological phenomena.     

Potential of membrane-mimetic polymers in membrane technology

Development of new generations of membranes with high degrees of permeabilities and controllable mass transport properties requires a fundamental understanding of the relationship between molecular structures and permeabilities. Initiation of interdisciplinary research in biology, biophysics, polymer and colloid chemistry is proposed to provide the insight to membrane transport processes at the molecular level. Mother nature's most talented transporter — the biological membrane — should inspire this endeavor. Following a survey of the properties of, and recognized transport mechanisms in, biomembranes, membrane-mimetic chemistry is introduced to serve as a bridge between biological and polymeric membranes. Surfactant aggregates — micelles, monolayers, organized multilayers (Langmuir—Blodgett films), bilayer lipid membranes (BLMs), vesicles and polymerized vesicles — are shown to be the media in membrane-mimetic chemistry. Properties of these organized surfactant assemblies are summarized. Emphasis is placed on the control of molecular transport in membrane-mimetic systems. Perspectives and prospectives of biomimetic membranology are discussed.     

A one-bead, one-stock solution approach to chemical genetics: part 2

BACKGROUND: Chemical genetics provides a systematic means to study biology using small molecules to effect spatial and temporal control over protein function. As complementary approaches, phenotypic and proteomic screens of structurally diverse and complex small molecules may yield not only interesting individual probes of biological function, but also global information about small molecule collections and the interactions of their members with biological systems. RESULTS: We report a general high-throughput method for converting high-capacity beads into arrayed stock solutions amenable to both phenotypic and proteomic assays. Polystyrene beads from diversity-oriented syntheses were arrayed individually into wells. Bound compounds were cleaved, eluted, and resuspended to generate 'mother plates' of stock solutions. The second phase of development of our technology platform includes optimized cleavage and elution conditions, a novel bead arraying method, and robotic distribution of stock solutions of small molecules into 'daughter plates' for direct use in chemical genetic assays. This library formatting strategy enables what we refer to as annotation screening, in which every member of a library is annotated with biological assay data. This phase was validated by arraying and screening 708 members of an encoded 4320-member library of structurally diverse and complex dihydropyrancarboxamides. CONCLUSIONS: Our 'one-bead, multiple-stock solution' library formatting strategy is a central element of a technology platform aimed at advancing chemical genetics. Annotation screening provides a means for biology to inform chemistry, complementary to the way that chemistry can inform biology in conventional ('investigator-initiated') small molecule screens.     

Chemische Biologie

Chemical Biology is a rapidly growing field at the interface of organic chemistry and cell biology. Chemical strategies are used to address biological questions not amenable to traditional genetic and biochemical techniques alone. Thc enormous potential of Chemical Biology is illustrated by four recent examples.     

Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry

Chemical biology and drug discovery are two scientific activities that pursue different goals but complement each other. The former is an interventional science that aims at understanding living systems through the modulation of its molecular components with compounds designed for this purpose. The latter is the art of designing drug candidates, i.e., molecules that act on selected molecular components of human beings and display, as a candidate treatment, the best reachable risk benefit ratio. In chemical biology, the compound is the means to understand biology, whereas in drug discovery, the compound is the goal. The toolbox they share includes biological and chemical analytic technologies, cell and whole-body imaging, and exploring the chemical space through state-of-the-art design and synthesis tools. In this article, we examine several tools shared by drug discovery and chemical biology through selected examples taken from research projects conducted in our institute in the last decade. These examples illustrate the design of chemical probes and tools to identify and validate new targets, to quantify target engagement in vitro and in vivo, to discover hits and to optimize pharmacokinetic properties with the control of compound concentration both spatially and temporally in the various biophases of a biological system.