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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：
Matthew Powner
金额：
$ 112.94万
依托单位：
University College London
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：
https://gtr.ukri.org/projects?ref=EP%2FX011755%2F1
关键词：
Nitriles prebiotic peptides synthetic applications.

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).

广泛接受的证据表明，35亿至34亿年前的沉积岩中存在生命，而且有迹象表明，地球上的生命在37亿年前就已经存在。大约39亿年前，地球遭受了强烈的流星和彗星撞击，最大的撞击可能使地球表面灭菌。生命是在上一次行星绝育撞击后开始的，但如何开始呢？对于那些试图阐明生命起源的人来说，这是一个终极问题，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。尽管这一目标已经追求了多年，并取得了一些重大进展，但仍然存在一些必须解决的问题。最近，“系统化学”的发展使生命研究的起源重新焕发生机，并重新发起了实验攻势。基于我们自己的工作，以及来自其他研究人员、同事和合作者的关键想法和结果，已经制定了一个关于生命起源的总体方案，其中氰化物和硫化物的反应性伴随并控制着生命摇篮中生命基本分子的选择性合成。硫化物和腈的特权反应性使该方案成为可能。在这项提议中，我们将进一步发展这种硫氰酸盐模型。我们将阐明腈化学是如何将生命中的丝氨酸蛋白氨基酸家族与一个普遍保守的酶辅助因子结合在一起的，以及如何通过在水中连接腈来提供获得扩展多肽的途径。独特的是，该项目将涉及将看似合理的益生化学反应应用于现代合成应用，包括合成和半合成酰胺、酰胺、多肽和蛋白质的新策略。我们将开发氰硫化情景的特权反应的合成应用，特别是催化多肽连接(CPL)，这是我们最近在探索生命的化学起源时阐明的。该反应作为催化合成多肽和酰胺的一种新的化学工具具有相当大的潜力。酰胺和多肽键的形成是化学和生物学中最重要的反应之一，美国化学学会绿色化学研究所(ACS Green Chemical Institute)确定的最大挑战是“形成酰胺避免使用原子经济性差的试剂”。在我们已发表工作的基础上，我们将开发一种用于酰胺和多肽连接的催化策略。开发(溶剂)水的新方法将对更广泛地实施绿色化学战略和英国的绿色经济至关重要，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，而且容易获得。目前使用的半合成延伸多肽和蛋白质的方法，即天然化学连接，在可形成的酰胺键的性质及其对固有不稳定的硫酯起始物质的要求方面有相当大的限制。CPL提供了绕过这些限制的尚未开发的潜力，为合成多肽和酰胺的制备提供了一个强大的工具。它不需要活化剂--形成酰胺所需的活化作用内置在动力学稳定的丁腈底物中。此外，我们将开发新的路线，以获得CPL的关键底物，即多肽和氨基腈，它们本身就是高价值的靶标(例如：萨格列汀、维达格列汀、帕昔洛韦)。