Novel vinyl-1,2,4-triazine linkers for protein modification and Tetra DVP for ADCs

第一年：一般技能培训和实验室轮换Years 2-4：该项目的目的是开发用于无金属催化剂的蛋白质修饰的化学品，用于开发蛋白质缀合物，如新型ADC，可能有助于其作为靶向药物的性能。多功能亲水性接头将被研究用于创造稳定和理想的均质药物;因此，使用单乙烯基-1，2，4-三嗪（MVT），一种新型的类连接体4，其对半胱氨酸具有选择性并且可以进行IEDDA反应，建立在Spring组的先前工作的基础上。一旦合成，将沿着研究MVTs与半胱氨酸的缀合动力学以及在赖氨酸存在下对半胱氨酸的选择性。将对半胱氨酸-MTV偶联物进行稳定性研究。将研究半胱氨酸-MVT缀合物和BCN衍生物之间的IEDDA速率。提出MVTs将具有与半胱氨酸的快速生物缀合动力学（与先前工作的单乙烯基1，3，5-三嗪的生物缀合动力学相当），对赖氨酸具有选择性，并且所得半胱氨酸-1，2，4-三嗪接头对细胞环境稳定。沿着新型MVT接头的新型类别，该项目寻求开发能够使用称为四-DVP 5的一种分子完全重新桥接抗体的二硫键的新型接头。这类连接器基于Spring Group以前开发的DVP连接器，并希望进一步开发该小组以前未发表的研究。这项工作旨在解决分子内环化和重新桥接问题，使四-DVP成为更有吸引力的接头。

Year 1: General skills training and lab rotationsYears 2-4: The aim of this project to develop chemical for metal catalyst-free protein modification for the development of protein conjugates such as novel ADCs that potentially help their performance in the use as targeted drugs.Multifunctional hydrophilic linkers are to be investigated for creating stable and ideally homogeneous drugs; therefore using mono vinyl-1,2,4-triazines (MVT) a novel of class linkers, 4, that are selective for cysteine and can perform IEDDA reactions, building on previous work in the Spring group. Once synthesised the conjugation kinetics of the MVTs with cysteine will be investigated along with the selectivity for cysteine in the presence of lysine. Stability investigation will be carried out on the cysteine-MTV conjugates. The rate of IEDDA between the cysteine-MVT conjugates and BCN derivatives will be investigated. It is proposed that the MVTs will have fast bioconjugation kinetics with cysteine (comparable to that of mono-vinyl 1,3,5-triazines of the previous work), be selective over lysine and the resultant cysteine-1,2,4-triazine linkers stable to the cellular environment. Along with the novel class of the novel MVT linkers this project looks to develop a novel class of linker capable of completely rebridging the disulfide bonds of an antibody using one molecule termed tetra-DVP 5. This class of linker is based on the DVP linkers previously developed in the Spring Group, and looks to further develop previous unpublished research from the group. This work looks to address the intramolecular cyclisation and rebridging issues to make tetra-DVP a more attractive linker.