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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 - 34亿年前的沉积岩中存在生命，而且有迹象表明，生命在37亿年前就已经在地球上存在了。大约39亿年前，地球遭受了强烈的陨石和彗星撞击，最大的撞击可能使地球表面绝迹。生命是在最后一次行星灭绝性撞击后开始的，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、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活跃起来，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思想和结果，我们已经形成了一个关于生命起源的总体方案，其中腈（氰化物）和硫化物的反应性伴随着并控制着生命摇篮中生命基本分子的选择性合成。由于硫化物和腈的特殊反应性，使该方案成为可能。在本提案中，我们将进一步发展这种氰硫模型。我们将阐明丁腈化学是如何将生命中的丝氨酸家族的蛋白质生成氨基酸与普遍保守的酶辅因子结合起来的，以及如何通过丁腈在水中的连接提供获得延伸肽的途径。独特的是，该项目将涉及将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。我们将开发氰磺化场景的特殊反应的合成应用，特别是催化肽连接（CPL），我们最近阐明了在追求生命的化学起源。该反应作为一种催化合成多肽和酰胺的新型化学工具具有相当大的潜力。酰胺和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）将“酰胺的形成避免原子经济性差的试剂”确定为有机化学的最大挑战。基于我们已发表的工作，我们将开发一种酰胺和肽连接的催化策略。利用（溶剂）水的新方法对绿色化学战略和英国绿色经济的更广泛实施至关重要，与酶和无机催化剂相比，我们将开发的小有机分子催化剂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。目前用于半合成延伸肽和蛋白质的方法，即天然化学连接，在可以形成的酰胺键的性质以及对固有不稳定的硫酯起始材料的要求方面具有相当大的局限性。CPL提供了未开发的潜力来规避这些限制，为合成肽和酰胺的制备提供了强大的工具。它不需要活化剂-形成酰胺所需的活化是内置在动力学稳定的腈底物。此外，我们将开发通往CPL关键底物的新途径，即肽腈和酰胺腈，它们本身就是高价值靶点（例如：沙格列汀，维格列汀，Paxlovid）。