Development of intracellular VNARs as novel tools to dissect intracellular biological processes

开发细胞内 VNAR 作为剖析细胞内生物过程的新工具

• 批准号: BB/R009112/1
• 负责人: Christopher Scott
• 金额: $ 44.16万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR009112%2F1
• 关键词: Development; intracellular; VNARs; novel; tools

The human body has over 20,000 genes, from which the proteins that make up each human cell are generated. The study of the roles of these proteins is therefore central to our understanding of life. The best way to determine the role of individual proteins is to block their function. As Scientists, we have a number of approaches for inhibiting protein functions, including synthetic compounds prepared by Chemists that bind to the proteins as well as a number of genetic approaches that delete or deplete the gene that generates a particular protein. However, useful as these approaches are, they are not without significant drawbacks. For example, synthetic compounds normally only work on proteins that have particular types of docking sites (e.g. deep pockets or grooves in their surfaces), and it is very difficult (and expensive) to develop compounds that selectively target specific proteins using this approach. Approaches that target a particular protein's gene can be more selective, but often the cell adapts to the loss of a protein in the time it takes to generate experimental models in which the gene is deleted or depleted; this can limit the usefulness of the information that can be gleaned from such studies.In this LINK proposal, we aim to bring together academic biological expertise at Queen's University Belfast (QUB) with the industrial expertise of Elasmogen Ltd to develop a completely new approach that will generate a novel type of molecule that can rapidly and highly specifically bind to and inhibit target proteins and thereby enable the function of those proteins to be accurately determined without the potentially confounding effects of the approaches described above. VNARs are antibodies produced by the immune system of sharks, and having evolved 420 million years ago, they are the oldest antibodies so far identified in vertebrates, and they are also the smallest. Despite their small size, VNARs have a unique structure that gives them a potentially greater number of ways of binding to target proteins than the antibodies produced by our own immune systems; this means that VNARs exhibit an extremely high degree of specificity and selectivity for their target proteins.Elasmogen have established a unique set of over 100 billion individual synthetic VNARs, each of which has a different structure and can therefore bind to a different protein. Given the sheer number of VNARs in the Elasmogen collection, it will be possible to identify individual VNARs that can bind to each protein in the human body. Elasmogen and others have already demonstrated the ability of VNARs to bind to proteins expressed on the surface of human cells and proteins secreted from cells. In this project QUB and Elasmogen will collaborate together to examine the possibility of adapting VNARs so that they can get inside cells and target intracellular proteins. If successful, would open up a number of hugely exciting possibilities, including:1. Establishment of a novel class of highly selective, potent intracellular inhibitors that could become powerful research tools for dissecting important biological processes.2. Evidence that intracellular VNARs could potentially be used as novel therapeutics in a range of diseases.

人体具有超过20,000个基因，从中产生了每个人类细胞的蛋白质。因此，研究这些蛋白质的作用对于我们对生命的理解至关重要。确定单个蛋白质作用的最佳方法是阻止其功能。作为科学家，我们采用了许多用于抑制蛋白质功能的方法，包括与蛋白质结合的化学家制备的合成化合物以及删除或耗尽产生特定蛋白质的基因的许多遗传方法。但是，与这些方法一样，它们并非没有明显的缺点。例如，合成化合物通常仅适用于具有特定类型的对接位点（例如，其表面上的深口袋或凹槽）的蛋白质，并且开发使用这种方法选择性地靶向特定蛋白质的化合物非常困难（而且昂贵）。靶向特定蛋白质基因的方法可以更具选择性，但是细胞通常适应于生成删除或耗尽基因的实验模型所花费的时间丢失。这可能会限制可以从此类研究中收集的信息的有用性。在该链接建议中，我们旨在将贝尔法斯特皇后大学（QUB）的学术生物学专业知识与Elasmogen LTD的工业专业知识结合在一起，以开发出一种全新的方法，以开发一种可以快速地确定蛋白质的新型分子的新方法，以确定蛋白质，并确定这些蛋白质的启发，并启用这些蛋白质的启动，并启用这些功能，使这些蛋白质的启动能够确定，并且可以使这些蛋白质具有功能，从而可以使这些蛋白质具有功能，从而可以使这些蛋白质具有功能，从而可以实现功能的功能，使得能够实现这些功能的功能。上述方法的影响。 VNAR是由鲨鱼免疫系统产生的抗体，并且在4.2亿年前进化，它们是迄今为止在脊椎动物中鉴定出的最古老的抗体，它们也是最小的抗体。尽管VNAR的尺寸很小，但它们的结构具有独特的结构，可以使它们与靶蛋白的结合方式比我们自己的免疫系统产生的抗体更大。这意味着VNAR对其靶蛋白具有极高的特异性和选择性。外源原来建立了一组超过1000亿个单独的合成VNAR，每个VNAR都具有不同的结构，因此可以与不同的蛋白质结合。鉴于弹性原收集中的VNAR数量庞大，可以识别可以与人体中每种蛋白质结合的单个VNAR。弹性原和其他人已经证明了VNAR与在细胞中分泌的人类细胞表面和蛋白质表面表达的蛋白质结合的能力。在这个项目中，Qub和Elasmogen将共同协作，以检查适应VNAR的可能性，以便它们可以进入细胞并靶向细胞内蛋白。如果成功的话，将打开许多令人兴奋的可能性，包括：1。建立一种新型的高度选择性，有效的细胞内抑制剂，这些抑制剂可能成为剖析重要生物学过程的强大研究工具。2。细胞内VNAR的证据可能可能被用作各种疾病的新型治疗剂。

项目成果

FLIP(L): the pseudo-caspase.

• DOI: 10.1111/febs.15260
• 发表时间: 2020-10
• 期刊: The FEBS journal
• 作者: Smyth P;Sessler T;Scott CJ;Longley DB
• 通讯作者: Longley DB

Development of next generation nanomedicine-based approaches for the treatment of cancer: we've barely scratched the surface.

• DOI: 10.1042/bst20210343
• 发表时间: 2021-11-01
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Tracey SR;Smyth P;Barelle CJ;Scott CJ
• 通讯作者: Scott CJ

Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy.

• DOI: 10.3389/fphar.2023.1296567
• 发表时间: 2023
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6