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

第1年：一般技能培训和实验室轮换第2-4年：本项目的目标是开发化学对金属无催化剂的蛋白质修饰，以开发蛋白质偶联物，例如潜在有助于其作为靶向药物使用的新型ADC。将研究多功能亲水连接物以创建稳定和理想的均一药物；因此，使用单乙烯基三嗪(MVT)，这是一种新型的类别连接物，4，对半胱氨酸具有选择性，可以执行IEDDA反应，建立在Spring小组先前工作的基础上。一旦合成，将研究MVTS与半胱氨酸的结合动力学，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。半胱氨酸-MVT偶联物和BCN衍生物之间的IEDDA速率将被研究。认为MVTS与半胱氨酸具有快速的生物偶联动力学(与前人工作中的单乙烯基1，3，5-三嗪相当)，对赖氨酸和所生成的对细胞环境稳定的半胱氨酸-1，2，4-三嗪连接物具有选择性。除了新型的MVT连接体，该项目还希望开发一种新的连接体，能够使用一种名为TETRA-DVP 5的分子完全重新桥接抗体的二硫键。这类连接体是基于Spring Group以前开发的DVP连接体，并希望进一步发展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联问题，使四-DVP成为更有吸引力的连接体。

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of linker is based on the DVP linkers previously developed in the Spring Group, and looks to further develop previous unpublished research from the group.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.