Nitriles: from prebiotic peptides to synthetic applications.
腈:从益生元肽到合成应用。
基本信息
- 批准号:EP/X011755/1
- 负责人:
- 金额:$ 112.94万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2023
- 资助国家:英国
- 起止时间:2023 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Widely accepted evidence exists for life in 3.5-3.4 billion year old sedimentary rocks, and there are indications life was already established on Earth 3.7 billion years ago. Approximately 3.9 billion years ago the Earth was subjected to intense meteoritic and cometary bombardment, and the largest impacts likely sterilised the Earth's surface. Life started after the last planet sterilising impact, but how? This is the ultimate question for those seeking to elucidate the origins of life, and one of the most profound and existential questions in science. The goal for those investigating the origins of life is to demonstrate, by experimentation, that life can emerge purely as a consequence of the rules of chemistry. Although this goal has been pursued for many years, and some major advances have been made, problems still remain that must be solved.Recently, the development of "systems chemistry" has reinvigorated origins of life research, and renewed experimental assault. Based upon our own work, and key ideas and results from other researchers, colleagues and collaborators, an overarching scheme for the origin of life has been developed, in which the reactivity of nitriles (cyanides) and sulfides chaperoned and controlled the selective synthesis of life's essential molecules in the cradle of life. The scheme is made possible by the privileged reactivity of sulfides and nitriles. In this proposal we will develop this cyanosulfidic model further. We will elucidate how nitrile chemistry unites life's serine family of proteinogenic amino acids with a universally conserved enzyme cofactor, as well as providing access to extended peptides via ligation of nitriles in water. Uniquely, this project will involve the application of plausible prebiotic chemical reactions to modern synthetic applications, including new strategies for the synthesis and semi-synthesis of amidines, amides, peptides and proteins. We will develop synthetic applications of the privileged reactions of the cyanosulfidic scenario, specifically Catalytic Peptide Ligation (CPL), which we recently elucidated in pursuit of the chemical origins of life. This reaction has considerable potential as a novel chemical tool for catalytic synthesis of peptides and amides. Amide and peptide bond formation is one of the most-important reactions in chemistry and biology, with 'amide formation avoiding poor atom economy reagents' identified by the ACS Green Chemical Institute as the top challenge for organic chemistry. Building on our published work, we will develop a catalytic strategy for amide and peptide ligation. New methodologies that exploit (solvent) water will be essential to the wider implementation of green chemistry strategies and the UK's green economy, and the small organic molecule catalysts we will develop are well-suited as artificial catalysts in comparison to enzymes and inorganic catalysts; they are simpler, typically non-toxic, and readily accessible. The currently used approach to the semi-synthesis of extended peptides and proteins, native chemical ligation, has considerable limitations in terms of the nature of the amide bond that can be formed and its requirement for inherently unstable thioester starting materials. CPL offers untapped potential to circumvent these limitations, providing a powerful tool for preparation of synthetic peptides and amides. It requires no activating agents - the activation required to form an amide is built into the kinetically stable nitrile substrate. Additionally, we will develop new routes to the key substrates for CPL, i.e. peptide- and amido-nitriles, which are high value targets themselves (examples include: Saxagliptin, Vildagliptin, Paxlovid).
在35 - 34亿年前的沉积岩中存在广泛接受的生命证据,并且有迹象表明生命在37亿年前已经在地球上建立。大约39亿年前,地球遭受了强烈的陨石和彗星轰击,最大的撞击可能使地球表面消毒。生命是在上次行星撞击后开始的,但如何开始的呢?这是那些寻求阐明生命起源的人的终极问题,也是科学中最深刻和最存在的问题之一。那些研究生命起源的人的目标是通过实验证明,生命可以纯粹作为化学规则的结果而出现。虽然这一目标已追求多年,并取得了一些重大进展,但仍存在一些必须解决的问题。最近,"系统化学"的发展重新激活了生命研究的起源,并重新发起了实验攻击。基于我们自己的工作,以及其他研究人员、同事和合作者的关键想法和结果,已经开发出了一个生命起源的总体方案,其中腈(氰化物)和硫化物的反应性陪伴和控制了生命摇篮中生命必需分子的选择性合成。该方案是可能的特权反应性的硫化物和腈。在本提案中,我们将进一步发展这种氰硫模型。我们将阐明腈化学如何将生命中的丝氨酸蛋白质氨基酸家族与普遍保守的酶辅因子结合起来,以及通过在水中连接腈来提供扩展肽。独特的是,该项目将涉及合理的益生元化学反应应用于现代合成应用,包括合成和半合成脒,酰胺,肽和蛋白质的新策略。我们将开发氰硫情景的特权反应的合成应用,特别是催化肽连接(CPL),我们最近在追求生命的化学起源中阐明了这一点。该反应具有相当大的潜力,作为一种新的化学工具,催化合成肽和酰胺。酰胺和肽键的形成是化学和生物学中最重要的反应之一,ACS绿色化学研究所将"避免原子经济性差的试剂的酰胺形成"确定为有机化学的首要挑战。在我们已发表的工作的基础上,我们将开发一种用于酰胺和肽连接的催化策略。利用(溶剂)水的新方法对于更广泛地实施绿色化学战略和英国的绿色经济至关重要,并且我们将开发的小有机分子催化剂与酶和无机催化剂相比非常适合作为人工催化剂;它们更简单,通常无毒,并且容易获得。目前使用的延伸肽和蛋白质的半合成方法,天然化学连接,在可以形成的酰胺键的性质及其对固有不稳定的硫酯起始材料的要求方面具有相当大的限制。CPL提供了未开发的潜力,以规避这些限制,提供了一个强大的工具,用于制备合成肽和酰胺。它不需要活化剂-形成酰胺所需的活化作用被构建到动力学稳定的腈底物中。此外,我们将开发CPL关键底物的新途径,即肽腈和氨基腈,它们本身就是高价值靶标(例如:沙格列汀、维达利、Paxlovid)。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Prebiotically plausible chemoselective pantetheine synthesis in water.
水中化学选择性泛茶氨酸的合成在生物起源前是合理的。
- DOI:10.1126/science.adk4432
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Fairchild J
- 通讯作者:Fairchild J
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Matthew Powner其他文献
Matthew Powner的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Matthew Powner', 18)}}的其他基金
An Investigation of Multicomponent Azole Chemistry within a Generational System for the Expression the Canonical Genetic Structures
代系系统内多组分唑化学的研究,用于表达典型的遗传结构
- 批准号:
EP/K004980/1 - 财政年份:2013
- 资助金额:
$ 112.94万 - 项目类别:
Fellowship
相似海外基金
Non-nutritive sweetener consumption during pregnancy and child body mass index: can postnatal fibre consumption mitigate potential risks?
怀孕期间的非营养性甜味剂消费和儿童体重指数:产后纤维消费可以减轻潜在风险吗?
- 批准号:
488069 - 财政年份:2023
- 资助金额:
$ 112.94万 - 项目类别:
Operating Grants
Investigating evolution of Martian atmosphere and production of prebiotic molecules using an atmospheric photochemistry model
使用大气光化学模型研究火星大气的演化和生命起源前分子的产生
- 批准号:
22KJ0314 - 财政年份:2023
- 资助金额:
$ 112.94万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Can Stellar Flares Activate Prebiotic Chemistry?
恒星耀斑可以激活前生命化学吗?
- 批准号:
2886131 - 财政年份:2023
- 资助金额:
$ 112.94万 - 项目类别:
Studentship
Nanoscale elucidation of prebiotic chemistry under early earth conditions
早期地球条件下生命起源化学的纳米级阐明
- 批准号:
23K17314 - 财政年份:2023
- 资助金额:
$ 112.94万 - 项目类别:
Grant-in-Aid for Challenging Research (Pioneering)
A randomized, double-blind, placebo-controlled, clinical trial of a probiotic/prebiotic supplement for the dietary management of age-related bone loss.
益生菌/益生元补充剂用于饮食管理与年龄相关的骨质流失的随机、双盲、安慰剂对照临床试验。
- 批准号:
10733549 - 财政年份:2023
- 资助金额:
$ 112.94万 - 项目类别:
Mathematical Modeling of the Impacts of Prebiotic Dietary Intervention on Immunomodulation During Estrogen Deficiency
雌激素缺乏期间益生元饮食干预对免疫调节影响的数学模型
- 批准号:
10593502 - 财政年份:2023
- 资助金额:
$ 112.94万 - 项目类别:
Development of Science-based Design Space for solid dosage forms with a combinational probiotic and prebiotic formulations
开发基于科学的设计空间,用于益生菌和益生元组合配方的固体剂型
- 批准号:
2692664 - 财政年份:2022
- 资助金额:
$ 112.94万 - 项目类别:
Studentship
Prebiotic Activity of Pinto Beans Reduces Neuroinflammation in Estrogen Deficiency
斑豆的益生元活性可减少雌激素缺乏症的神经炎症
- 批准号:
10715516 - 财政年份:2022
- 资助金额:
$ 112.94万 - 项目类别:
DNA Amplification Beyond Biology: Achieving Self-Replication in Nano-Assemblies and Prebiotic Model Systems
超越生物学的 DNA 扩增:在纳米组件和益生元模型系统中实现自我复制
- 批准号:
RGPIN-2020-05976 - 财政年份:2022
- 资助金额:
$ 112.94万 - 项目类别:
Discovery Grants Program - Individual
Understanding of the diversity of prebiotic chemistries and emergence of molecular systems in various planetary environments in the Solar System
了解生命起源前化学的多样性以及太阳系各种行星环境中分子系统的出现
- 批准号:
22K21344 - 财政年份:2022
- 资助金额:
$ 112.94万 - 项目类别:
Fund for the Promotion of Joint International Research (International Leading Research )