九层之台,起于累土——从化学生物学成长浅析基金支持对交叉学科的引领作用

化学生物学是化学与生物学、医学等高度交叉的新兴学科.20世纪末开始,传统学科间的深度融合已经成为科学发展的必然,化学生物学的出现顺应了这种趋势,为生命过程研究带来新的视角,为化学带来新的挑战和机遇.尽管我国化学生物学研究起步略晚于欧美,但是在学科建设过程中得到国家各个层面的关注和支持,发展势头迅猛.2002年国家自然科...     

前言

<正>化学生物学和纳米生物学是两个充满活力和挑战的相近领域.化学和纳米科学与生命科学的交叉,为生物学问题的研究提供了新方法和新技术,促进产生新的科学发现,实现生命过程可视、可控、可创造的新可能性.随之,对生物学过程的研究与探索也促进了化学学科和纳米科学的发展,导致新规律和新理论的出现.交叉学科研究的挑战之一在于需要学习与理解其他领域的知识和思想.我们需要了解哪些是重要而有意     

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.     

化学生物学新前沿——化学蛋白质组学

随着包括人类在内的主要模式生物的基因组计划的完成,生命科学的研究重心转向蛋白质组的研究--在对应基因组的整体蛋白质水平上系统研究调控细胞生命活动的蛋白质.化学蛋白质组学是化学生物学在后基因组时代的最新发展:化学蛋白质组学利用化学小分子为工具和手段,以基于靶蛋白质功能的新战略探测体内蛋白质组,是新一代的功能蛋白质组学.本文综述了化学蛋白质组学的最新进展、有关技术及其在生物医学和药物研发等方面的应用,并对化学蛋白质组学的发展趋势和前景进行了讨论.     

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。     

化学生物学的奠基者--施瑞伯教授

化学生物学是20世纪90年代出现的交叉学科,主要是利用小分子来研究生命问题,哈佛大学的S.L.施瑞伯教授是这一领域的主要奠基者,经过十几年的研究已经使人们对生命过程有了更为全面的理解,从而对一些疾病的治疗带来了新的希望,因此化学生物学成为了当前比较热门的领域。     

光敏开关及其在化学生物学中的应用*

近年来随着生物医学技术的发展,人们需要越来越细致地在分子水平上研究各种生命过程。为了能够实现实时原位地观察活细胞或组织中的生命化学过程,需要使用以物理方法来选择性激活的分子探针。以共聚焦激光技术为基础的光敏开关能很好地解决这一问题。迄今,发展和用于光敏开关的光敏剂已成为化学生物学研究的重要方向。本文重点总结了各种可应用于共聚焦激光系统的单、双光子光敏基团（单光子的光敏基团主要有：硝基苯类、香豆素类等;双光子光敏基团主要有：香豆素类、喹啉类及吲哚衍生物类）以及这几类光敏基团在化学生物学中的应用。     

蛋白质分子印迹聚合物研究

分子识别现象在生命过程中扮演着极其重要的角色,对此进行研究和探索是化学和生物学领域的核心课题,制备具有分子识别能力的人工受体是对该领域科学工作者的一个持久挑战．为此,相关研究人员进行了多方努力,创造性地发展了许多崭新的方法和手段,其中的分子印迹聚合物制备技术就是这些方法和手段中的一种.     

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。     

基于活性的蛋白质组分析

众多物种基因组解码工作的完成极大地丰富了我们对这些生命体系组成复杂度的认知, 然而下一个更为严峻的挑战是如何快速准确地解析这些基因编码蛋白的分子功能, 这也是当前蛋白质组学领域亟待解决的一个重要科学问题. 基于活性的蛋白质组分析是近些年来一项新兴的技术平台, 它致力于在复杂的生命体系中系统地鉴定某类具有特定功能的蛋白质分子. 在本篇短综述中, 我们将对该化学生物学技术的发展做一个简要的回顾, 重点介绍该技术在未知蛋白的功能解析、小分子抑制剂的筛选以及活性小分子靶标蛋白的鉴定等方面的工作, 最后将对该技术未来发展的走向及其拓展应用做前瞻性的讨论.     

Seeing the light: luminescent reporter gene assays

The luminescent reporter gene assay (LRGA) is arguably the most prominent type of reporter gene assay used in biomolecular and pharmaceutical development laboratories. Part of this popularity is due to the high signal associated with luciferases, the foundation of this technology. This feature makes them ideally suited for high throughput screening applications where potentially millions of chemical compounds can be analyzed in a given assay. Recent technical advancements that enhance signal stability of the luciferases along with development and commercialization of multiple forms of luciferases, their respective substrates, and improvements in expression vectors for reporter gene assay (RGA) applications have broadened their use. While the practical challenges related to the application of luminescent technology in a laboratory setting have been overcome, there remains much to do in laying a systematic approach towards the construction of RGAs, which are essential to the elucidation of the basic biology for genes of interest. This mini-review aims at giving a birds-eye view of the available luciferases, substrates and other luminescent technologies available and provides a general blueprint as well as practical considerations for constructing and interfacing RGAs with chemical biology and functional genomics for the elucidation of fundamental biological questions and for biomedical research.     

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.     

化学生物学实验的教学实践及其安全管理

作为化学领域的新兴二级学科,化学生物学利用化学的原理、方法和具有生物活性的化合物来研究生命过程中的问题。本文主要介绍了清华大学为"学堂人才计划"学生培养建立的实验课程平台——"化学生物学实验"课程的教学实践、体会和安全管理。     

Characterization and quantification of biological micropatterns using Cluster-SIMS

Micropatterning is used widely in biosensor development, tissue engineering and basic biology. Creation of biological micropatterns typically involves multiple sequential steps that may lead to cross-contamination and may contribute to sub-optimal performance of the surface. Therefore, there is a need to develop novel strategies for characterizing location-specific chemical composition of biological micropatterns. In this paper, C(60) (+) ToF-SIMS operating in the event-by-event bombardment-detection mode was used for spatially resolved chemical analysis of micropatterned indium tin oxide (ITO) surfaces. Fabrication of the micropatterns involved multiple steps including self-assembly of poly (ethylene glycol) (PEG)-silane, patterning of photoresist, treatment with oxygen plasma and adsorption of collagen (I). The ITO surfaces were analyzed with 26 keV C(60) (+)SIMS run in the event-by-event bombardment-detection mode at different steps of the modification process. We were able to evaluate the extent of cross-contamination between different steps and quantify coverage of the immobilized species. The methodology described here provides a novel means for characterizing the composition of biological micropatterns in a quantitative and spatially-resolved manner.     

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.     

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.     

Photo-controllable bioorthogonal chemistry for spatiotemporal control of bio-targets in living systems

The establishment of bioorthogonal chemistry is one of the most significant advances in chemical biology using exogenous chemistry to perturb and study biological processes. Photo-modulation of biological systems has realized temporal and spatial control on biomacromolecules in living systems. The combination of photo-modulation and bioorthogonal chemistry is therefore emerging as a new direction to develop new chemical biological tools with spatiotemporal resolution. This minireview will focus on recent development of bioorthogonal chemistry subject to spatiotemporal control through photo-irradiation. Different strategies to realize photo-control on bioorthogonal bond-forming reactions and biological applications of photo-controllable bioorthogonal reactions will be summarized to give a perspective on how the innovations on photo-chemistry can contribute to the development of optochemical biology. Future trends to develop more optochemical tools based on novel photochemistry will also be discussed to envision the development of chemistry-oriented optochemical biology.

The establishment of photo-controllable bioorthogonal chemistry is one of the most significant advances in chemical biology to perturb and study biological processes.     

Microfluidic chip: Next-generation platform for systems biology

Systems biology advocates the understanding of biology at the systems-level, which requires massive information of correlations among individual components in complex biological systems. Such comprehensive investigation entails the use of high-throughput analytical tools. Microfluidic technology holds high promise to facilitate the progress of biology by enabling miniaturization and upgrading of current biological research tools due to its advantages such as low sample consumption, reduced analysis time, high-throughput and compatible sizes with most biological samples. In this article, we documented the recent applications of microfluidic chips in biological researches at the molecular level, cellular level and organism level, serving the purpose for systems-level understanding of biology.     

Expanded utility of the native chemical ligation reaction

The post-genomic era heralds a multitude of challenges for chemists and biologists alike, with the study of protein functions at the heart of much research. The elucidation of protein structure, localization, stability, post-translational modifications, and protein interactions will steadily unveil the role of each protein and its associated biological function in the cell. The push to develop new technologies has necessitated the integration of various disciplines in science. Consequently, the role of chemistry has never been so profound in the study of biological processes. By combining the strengths of recombinant DNA technology, protein splicing, organic chemistry, and the chemoselective chemistry of native chemical ligation, various strategies have been successfully developed and applied to chemoselectively label proteins, both in vitro and in live cells, with biotin, fluorescent, and other small molecule probes. The site-specific incorporation of molecular entities with unique chemical functionalities in proteins has many potential applications in chemical and biological studies of proteins. In this article, we highlight recent progress of these strategies in several areas related to proteomics and chemical biology, namely, in vitro and in vivo protein biotinylation, protein microarray technologies for large-scale protein analysis, and live-cell bioimaging.