Investigations into aryl nitriles for protein modification via an untapped mode of reactivity

通过未开发的反应模式研究芳基腈用于蛋白质修饰

• 批准号: EP/X037819/1
• 负责人: James Baker
• 金额: $ 67.48万
• 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: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX037819%2F1
• 关键词: Investigations; into; aryl; nitriles; protein

The controlled chemical modification of peptides and proteins is a crucial underpinning technology for a number of rapidly growing areas in chemical biology and the biomedical sciences. Applications include: antibody-drug conjugates (ADCs) and related targeted therapeutics; radiolabelled proteins for imaging; covalent inhibitors in drug discovery; stapled peptides as stabilised therapeutics; and numerous nanoparticle conjugates/other nanotechnologies. The discovery, development or repurposing of chemical reactions to enable the construction of such conjugates in new ways can be a key driving force behind innovations in the area. This is powerfully illustrated by the recent award of the 2022 Nobel Prize in Chemistry for the development of 'Click Chemistry' which has played a key role in dramatically enabling diverse applications. In this project we are hypothesising that a particular class of reagents, containing a nitrile functional group, could enable new modes of protein modification via an untapped mode of their reactivity, i.e. their reaction with two thiols consecutively. Once we have demonstrated the viability, efficiency and scope of these reactions, we will explore the new opportunities enabled. A key focus application will be to enable the construction of ADCs, demonstrating that these nitriles offer a unique dynamic mechanistic pathway to highly homogenous, site-selective antibody conjugates. ADCs represent one of the most exciting classes of new targeted anti-cancer therapeutics, with 13 ADCs now having achieved clinical approval. They aim to overcome the limitations of existing chemotherapeutics by delivering the cytotoxic drug specifically to the cancer cells, and thus reducing the side-effects associated with damaging healthy tissue. To maximise the chances for ADCs achieving their therapeutic potential, their design and chemical construction must be improved. As such, the methods developed in this project aim to provide an extremely convenient and efficient approach to carry out the chemical attachment to antibodies in a highly controlled manner. Furthermore, the reagent class we are developing would be the first of a kind in enabling controlled attachment to two different amino-acids on the surface of antibodies simply by tuning the molecular design; by strategies known as 'disulfide stapling' and 'cysteine-to-lysine transfer'. This will also enable us to carry out iterations of controlled chemical modification, accessing multifunctional conjugates which represent an enticing prospect for the next generation of antibody-based therapeutics.In a second key demonstration of applications enabled by the chemical methods pioneered in this project, we aim to show that nitrile reagents could also offer a unique ability to selectively inhibit specific classes of enzymes. Such covalent inhibitors are a growth area in drug discovery, as they offer the prospect of prolonged therapeutic effects. However, selectivity is vital in such strategies. We aim to show that reagents which form stabilised adducts only when they react with two proximal cysteine amino-acids, form a new mechanistic class of selective inhibitors for enzymes. Our overall approach within this project is to explore and tune an untapped, fascinating chemical reaction, and to demonstrate that it offers significant new opportunities in protein modification. In so doing, this project will offer insights stretching from fundamental chemistry to therapeutic development.

肽和蛋白质的受控化学修饰是化学生物学和生物医学科学中许多快速生长的地区的至关重要的基础技术。应用包括：抗体 - 药物缀合物（ADC）和相关的靶向治疗剂；用于成像的放射性标记蛋白；药物发现中的共价抑制剂；钉肽作为稳定的治疗剂；以及许多纳米颗粒联合/其他纳米技术。化学反应的发现，开发或重新利用以使这种结合者以新的方式构建可能是该地区创新背后的关键推动力。最近获得2022年诺贝尔化学奖的“点击化学”奖的奖项有力地说明了这一点，该奖项在极大地启用了多样化的应用中发挥了关键作用。在这个项目中，我们假设一种特定类别的试剂（包含硝酸盐功能组）可以通过未开发的反应性模式来实现新的蛋白质修饰模式，即它们与两个硫醇连续的反应。一旦我们证明了这些反应的生存能力，效率和范围，我们将探索启用的新机会。一个关键的重点应用是实现ADC的构建，表明这些硝化物为高度同质的现场选择性抗体结合物提供了独特的动态机械途径。 ADC代表了最令人兴奋的新目标抗癌治疗方法之一，现在有13种ADC已获得临床批准。他们的目的是通过将细胞毒性药物专门提供给癌细胞，从而减少与损害健康组织有关的副作用，从而克服现有化学治疗剂的局限性。为了最大程度地提高ADC获得其治疗潜力的机会，必须改善其设计和化学结构。因此，该项目中开发的方法旨在提供一种非常方便，高效的方法，以高度控制的方式对抗体进行化学附件。此外，我们正在开发的试剂类将是一种仅通过调整分子设计来启用抗体表面上两个不同氨基酸的连接的第一个。通过称为“二硫键钉”和“半胱氨酸到赖氨酸转移”的策略。这也将使我们能够进行受控化学修饰的迭代，访问多功能结合物，这代表了下一代基于抗体的疗法的诱人前景。目的是表明硝酸试剂还可以提供独特的能力来选择性地抑制特定类别的酶。这种共价抑制剂是药物发现的一个生长区域，因为它们提供了长期治疗作用的前景。但是，选择性对于此类策略至关重要。我们的目的是表明，只有在与两个近端半胱氨酸氨基酸反应时形成稳定加合物的试剂形成酶的选择性抑制剂的新机理类别。我们在该项目中的整体方法是探索和调整未开发的，引人入胜的化学反应，并证明它在蛋白质修饰方面提供了重要的新机会。这样一来，这个项目将提供从基本化学到治疗发展的见解。