Next Generation Bicycle Scaffolds: Phage Selection With Added Functionality

下一代自行车支架：具有附加功能的噬菌体选择

• 批准号: 2870155
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2870155
• 关键词: Next; Generation; Bicycle; Scaffolds; Phage

BicycleTx Ltd is a biotech company founded to develop a new therapeutic modality based on thioether bridged bicyclic peptides (Bicycles). Their technology is based on screening synthetically constrained phage encoded combinatorial peptide libraries.1 M13 phage displaying short peptide libraries (9 - 20 residues) including three Cys residues are cross-linked through reaction of the Cys-SH with reactive functional groups on a C3-symmetrical small molecule scaffold to give conformationally constrained bicyclic peptides expressed on the pIII coat protein. These Bicycle libraries are then screened against a range of biological targets to identify peptide sequences with high affinity and selectivity. This powerful technology enables BicycleTx to develop novel leads to tackle intractable diseases and undruggable targets in oncology, immunoncology and antimicrobial therapeutics.2A critical limitation is that it is not currently possible to screen Bicycle libraries with additional functionality, such as cell penetrating peptides, lipids to anchor the Bicycles to membranes, or siderophores for active uptake to Gram -ve bacteria. This would make it possible to screen the resulting Bicycle-conjugated libraries for binding to their targets, where the selection process would inherently include cell penetration, membrane surface localisation, or uptake to Gram -ve bacteria.In this project, the student will design and synthesise novel bifunctional, C3-symmetric scaffolds bearing (i) three identical groups for covalent attachment to the three phage Cys-SH and (ii) one or three "click" handles to attach additional functionality. These Next Generation C3-symmetric Bicycle scaffolds will be designed with alkylating groups that can be reacted with the phage peptide under mild aqueous conditions; the click handles will allow biorthogonal attachment of lipids, peptides and siderophores. Structurally simple scaffolds will be used to avoid side-reactions with other regions of the phage peptide. Two types of scaffolds will be synthesised and tested: rigid scaffolds based on an adamantane core, which will have three symmetrical alkylating groups and a fourth point of attachment for bioconjugation of the additional functionality; and symmetrical cycle hexapeptide-based scaffolds with three groups that can be conjugated to the Cys-SH and three for attachment of the additional groups. The student will then test these scaffolds with phage libraries to optimise the efficiency of conjugation to the scaffolds, and may then screen a library containing one of these scaffolds for binding to a therapeutically relevant target. NMR/X-ray studies of high-affinity Bicycles will be carried out to determine the effects of the new scaffolds on the conformation of the constrained peptides.These next generation Bicycles will combine the pharmacological properties of a biologic with the pharmacokinetic and synthetic advantages of a small molecule, enabling a range of therapeutically relevant targets to be tackled, including many that have so far been undruggable with small molecules. The proposed work is a clear fit to the BBSRC Advancing the frontiers of bioscience discovery objective (in particular the transformative technologies priority). It is aligned to the Pharmaceuticals and Technology Development research areas, and has potential impact relating to the combatting antimicrobial resistance priority area.1. Nature Chem Biol 5, 502 (2009) 2. J Med Chem 63, 4107 (2020)

BicycleTx有限公司是一家生物技术公司，成立的目的是开发一种基于硫醚桥联双环肽(自行车)的新治疗方式。他们的技术是基于筛选合成受限噬菌体编码的组合多肽库。1 M13噬菌体展示短肽文库(9-20个残基)，包括三个半胱氨酸残基，通过C3对称小分子支架上的活性官能团与Cys-SH反应交联，得到表达在PIII外壳蛋白上的构象受限双环肽。然后根据一系列生物靶标对这些自行车文库进行筛选，以确定具有高亲和力和选择性的多肽序列。这项强大的技术使BicycleTx能够开发新的线索，以解决肿瘤学、免疫肿瘤学和抗微生物疗法中的疑难疾病和不可治疗的目标。2关键的限制是，目前无法筛选具有其他功能的自行车库，如细胞穿透肽、将自行车固定在膜上的脂类，或主动摄取革兰氏细菌的铁载体。在这个项目中，学生将设计和合成新型的双功能、C3对称的支架，这些支架包括(I)三个相同的基团用于共价连接到三个噬菌体Cys-SH上，以及(Ii)一个或三个“点击”手柄以附加额外的功能。这些新一代C3对称自行车支架的设计将带有烷基化基团，可以在温和的水条件下与噬菌体多肽反应；点击手柄将允许脂类、多肽和铁载体的双正交连接。结构简单的支架将被用来避免与噬菌体多肽的其他区域发生副反应。将合成和测试两种类型的支架：基于金刚烷核心的刚性支架，将有三个对称的烷基化基团和第四个附着点，用于附加功能的生物连接；对称环六肽支架，具有三个基团，可以连接到Cys-SH和三个附加基团的附着。然后，学生将用噬菌体文库测试这些支架，以优化与支架的结合效率，然后可能会筛选包含这些支架之一的文库，以结合到治疗相关的靶点。将对高亲和力自行车进行核磁共振/X射线研究，以确定新支架对受约束多肽构象的影响。这些下一代自行车将结合生物的药理学特性与小分子的药代动力学和合成优势，使一系列与治疗相关的靶点能够被攻克，包括许多迄今为止无法用小分子药物治疗的靶点。拟议的工作显然适合BBSRC推进生物科学发现目标的前沿(特别是变革性技术优先事项)。它与药品和技术开发研究领域保持一致，并对打击抗菌素耐药性优先领域产生潜在影响。自然化学生物5,502(2009)2.医学化学杂志63,4107(2020)