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

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of linker is based on the DVP linkers previously developed in the Spring Group, and looks to further develop previous unpublished research from the group.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