From Total Synthesis-Inspired Methodology to Anti-HIV therapy
从全合成启发的方法到抗 HIV 治疗
基本信息
- 批准号:EP/E055273/1
- 负责人:
- 金额:$ 84.94万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Fellowship
- 财政年份:2007
- 资助国家:英国
- 起止时间:2007 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Organic chemistry provides a bridge between the physical world of atoms, molecules and their reactions, and the biological sciences, with one area of particular importance being the development of new medicines. Many drugs are originally inspired by 'natural products' / molecules refined by Nature over millions of years, which can have potent, specific biological activity against human diseases. As such, natural products represent highly advanced starting points for pharmaceutical research; however, their development as drug leads can be hampered by low natural abundance. One solution (which avoids decimation of the natural habitat) is the artificial preparation, or 'total synthesis' of the natural product. Historically, this process can take many years, a timescale which cannot satisfy the requirements of automated pharmaceutical screening. However, the application of improved, efficient chemical methods which enable rapid and scalable syntheses of these natural medicines (and non-natural 'analogues' with improved efficacy), is now an aim that is within the grasp of the organic chemist. Natural products chemistry thus stands on the brink of being re-embraced by the pharmaceutical community; this proposal aims to show that the natural product target itself is just the beginning of what an organic chemist can deliver.Traditionally, organic chemistry can be divided into two schools of research. The development of new reactions, which is fundamental to improving the efficiency of chemical synthesis, investigates new ways to form bonds between atoms. Often there is no specific target, and researchers can resort to scouring a vast array of natural products for one which will showcase their methodology. By contrast, in the field of total synthesis of structurally challenging molecules (which provides the ultimate testing ground for methodology), chemists tend to use known methods to forge the most efficient path they are able to a given target. The challenge of synthesis itself usually dictates that the choice of reaction is one with precedent and reliability.This proposal seeks to reverse this accepted order of reaction development: Natural products are seen as the inspiration for new reactions, rather than an arbitrary setting. Biologically important targets will be selected, and provide the impetus for the invention of an efficient and appealing synthetic transformation. Following development in a general setting, this method will then be applied in the context it was intended / a total synthesis of the natural product and analogues. Two projects which demonstrate the potential for natural products to initiate the development of useful, general reactions with broad applicability are proposed: Cepacin A, a potent antibiotic which contains an intriguing unsaturation motif, is the inspiration for a novel synthesis of chiral allenes. Lancifodilactone G and rubriflordilactone A, which possess anti-HIV properties, are the basis for an innovative route to bi- or tricyclic molecules.My proposal also details a collaborative project towards new methods for HIV inhibition. A currently uninvestigated area of the HIV life cycle is the 'packaging' of viral RNA into new virus particles. Packaging is initiated by binding of the viral protein Gag to a region of the viral RNA called psi. It is known that psi, and a truncated analogue, are bound specifically by a region of Gag that contains amino acids with nucleophilic sidechains. We intend to design psi analogues containing an electrophilic site, which will bind to Gag and place this site in proximity to the nucleophilic sidechain amino acids, leading to the formation of a covalent bond, irreversible binding of Gag, and inhibition of packaging. This is an exciting and unexplored area of chemical biology which harnesses the expertise of both the organic chemist and the virologist, and could have implications for the design of inhibitors for other virus specific RNA-protein interactions.
有机化学在原子、分子及其反应的物理世界与生物科学之间架起了一座桥梁,其中一个特别重要的领域是新药的开发。许多药物最初的灵感来自于数百万年来大自然提炼的“天然产物”/分子,它们对人类疾病具有有效的、特异的生物活性。因此,天然产物代表了药物研究的高度先进的起点;然而,它们作为药物先导的发展可能会受到天然丰度低的阻碍。一种解决方案(避免自然栖息地的大量减少)是人工制备,或天然产品的“全合成”。从历史上看,这个过程可能需要很多年,这是一个无法满足自动化药物筛选要求的时间尺度。然而,应用改进的、有效的化学方法,使这些天然药物(和具有改进功效的非天然“类似物”)的快速和可扩展的合成成为有机化学家掌握的目标。天然产物化学因此站在被重新接受的边缘由制药界;这个提议旨在表明,天然产物的目标本身只是一个有机化学家可以提供什么的开始。传统上,有机化学可以分为两个学校的研究。新反应的发展是提高化学合成效率的基础,研究了原子之间形成键的新方法。通常没有特定的目标,研究人员可以求助于搜索大量的天然产品,以展示他们的方法。相比之下,在结构上具有挑战性的分子的全合成领域(这为方法学提供了最终的测试基础),化学家倾向于使用已知的方法来打造他们能够达到给定目标的最有效的路径。合成本身的挑战通常决定了反应的选择是有先例和可靠性的。这个提议试图扭转这种公认的反应发展顺序:天然产物被视为新反应的灵感,而不是任意设置。生物学上重要的目标将被选择,并提供一个有效的和有吸引力的合成转化的发明的动力。在一般环境中开发之后,该方法将应用于其预期/天然产物和类似物的全合成。提出了两个项目,展示了天然产物的潜力,以启动开发有用的,具有广泛适用性的一般反应:头孢菌素A,一种有效的抗生素,其中包含一个有趣的不饱和基序,是一种新的合成手性联烯的灵感。Lancifodilactone G和rubriflodilactone A具有抗艾滋病病毒的特性,是双环或三环分子的创新路线的基础。我的提案还详细介绍了一个合作项目,旨在开发新的艾滋病病毒抑制方法。HIV生命周期的一个目前尚未研究的领域是病毒RNA“包装”成新的病毒颗粒。包装是由病毒蛋白Gag与病毒RNA中称为psi的区域结合而启动的。已知psi和截短的类似物通过含有具有亲核侧链的氨基酸的Gag区域特异性结合。我们打算设计含有亲电子位点的psi类似物,其将与Gag结合并将该位点置于亲核侧链氨基酸附近,从而形成共价键,Gag的不可逆结合和包装的抑制。这是一个令人兴奋和未探索的化学生物学领域,它利用了有机化学家和病毒学家的专业知识,并可能对其他病毒特异性RNA-蛋白质相互作用的抑制剂的设计产生影响。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Selectivity in Transition Metal-catalyzed Cyclizations: Insights from Experiment and Theory.
过渡金属催化环化的选择性:实验和理论的见解。
- DOI:10.2533/chimia.2018.614
- 发表时间:2018
- 期刊:
- 影响因子:1.2
- 作者:Anderson EA
- 通讯作者:Anderson EA
Carbopalladation of bromoene-alkynylsilanes: mechanistic insights and synthesis of fused-ring bicyclic silanes and phenols
- DOI:10.1039/c4qo00123k
- 发表时间:2014-01-01
- 期刊:
- 影响因子:5.4
- 作者:Cordonnier, Marie-Caroline A.;Kan, S. B. Jennifer;Anderson, Edward A.
- 通讯作者:Anderson, Edward A.
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Edward Anderson其他文献
Buyer’s optimal information revelation strategy in procurement auctions
采购拍卖中买方最优信息披露策略
- DOI:
10.1016/j.ejor.2019.11.061 - 发表时间:
2020 - 期刊:
- 影响因子:6.4
- 作者:
Cheng Qian;Edward Anderson - 通讯作者:
Edward Anderson
<strong>Repurposing drugs for CLN1 Batten disease: An integrative drug discovery approach</strong>
- DOI:
10.1016/j.ymgme.2020.12.212 - 发表时间:
2021-02-01 - 期刊:
- 影响因子:
- 作者:
Ana C. Puhl;Patricia A. Vignaux;Eni Minerali;Jennifer J. Klein;Tammy M. Havener;Edward Anderson;Anthony J. Hickey;Sean Ekins - 通讯作者:
Sean Ekins
On the joint evaluation of absolute and relative deprivation
- DOI:
10.1007/s10888-013-9262-7 - 发表时间:
2013-12-20 - 期刊:
- 影响因子:2.400
- 作者:
Edward Anderson;Lucio Esposito - 通讯作者:
Lucio Esposito
A new model for cycles in retail petrol prices
- DOI:
10.1016/j.ejor.2010.10.009 - 发表时间:
2011-04-16 - 期刊:
- 影响因子:
- 作者:
Edward Anderson - 通讯作者:
Edward Anderson
Edward Anderson的其他文献
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{{ truncateString('Edward Anderson', 18)}}的其他基金
Thiophene dioxides: Versatile tools for ring synthesis
二氧化噻吩:环合成的多功能工具
- 批准号:
EP/X028674/1 - 财政年份:2023
- 资助金额:
$ 84.94万 - 项目类别:
Research Grant
New Directions in Bioisostere Research
生物等排体研究的新方向
- 批准号:
EP/S013172/1 - 财政年份:2019
- 资助金额:
$ 84.94万 - 项目类别:
Research Grant
Enabling precision distance measurements in long RNAs
实现长 RNA 的精确距离测量
- 批准号:
BB/R021848/1 - 财政年份:2018
- 资助金额:
$ 84.94万 - 项目类别:
Research Grant
A Unified, Practical Synthesis of Five-Membered Aromatic Heterocycles
五元芳香杂环的统一、实用合成
- 批准号:
EP/M019195/1 - 财政年份:2015
- 资助金额:
$ 84.94万 - 项目类别:
Research Grant
Cascade Catalysis: From Alkynes to Polycycles
级联催化:从炔烃到多环化合物
- 批准号:
EP/K005391/1 - 财政年份:2013
- 资助金额:
$ 84.94万 - 项目类别:
Research Grant
A Unified Route to Bicyclic Heterocycles: Synthesis and Applications
双环杂环化合物的统一路线:合成与应用
- 批准号:
EP/H025839/1 - 财政年份:2010
- 资助金额:
$ 84.94万 - 项目类别:
Research Grant
Application of Statistical Classification Analysis to Engineering Student Recruitment
统计分类分析在工科生招生中的应用
- 批准号:
0836028 - 财政年份:2009
- 资助金额:
$ 84.94万 - 项目类别:
Standard Grant
Refinement of Introductory Engineering Thermodynamics Computer-Based-Learning Modules
工程热力学入门学习模块的完善
- 批准号:
0089410 - 财政年份:2001
- 资助金额:
$ 84.94万 - 项目类别:
Standard Grant
Special Graudate Student Research Award
研究生特别研究奖
- 批准号:
8920758 - 财政年份:1989
- 资助金额:
$ 84.94万 - 项目类别:
Standard Grant
Engineering Creativity Award: Laser Induced Breakup or & Atomization of Small Liquid Jets
工程创意奖:激光诱导破碎或
- 批准号:
8811625 - 财政年份:1988
- 资助金额:
$ 84.94万 - 项目类别:
Continuing Grant
相似国自然基金
新型滤波器综合技术-直接综合技术(Direct synthesis Technique)的研究及应用
- 批准号:61671111
- 批准年份:2016
- 资助金额:58.0 万元
- 项目类别:面上项目
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