EAGER: Templated Synthesis of Protein Conjugates

Clarkson University, Potsdam NY

Investigators

Abstract

In this project funded by the Chemical Synthesis Program of the Chemistry Division, Professor Artem Melman of the Department of Chemistry & Biomolecular Science at Clarkson University will explore the development of new methods for the site specific derivatization of recombinant proteins. Current methods for covalent derivatization of proteins are not selective, producing complex mixtures of protein conjugates. The proposed approach will rely on formation of metal complexes with the hexahistidine sequence that is present in most recombinant proteins as a template for subsequent intramolecular alkylation of one of the histidine residues of the hexahistidine sequence. The project will involve study of ternary metal complexes of hexahistidine with other chelate ligands, design and synthesis of histidine alkylating agents, and chemoselectivity of their reactions with different nucleophiles. Based on these studies, new hexahistidine alkylating reagents will be prepared and tested for selective derivatization of model recombinant proteins. This work is anticipated to lead to efficient methods for derivatization of proteins and production of functional protein conjugates. Development of these methods will have impact on several research fields using chemically modified proteins including biochemistry, synthetic biology, and medicinal chemistry. Possible applications of new protein conjugates include new targeted drug delivery, early diagnostics of diseases, and determination of structure and functions of proteins in biological systems. In addition, this project will provide advance training of undergraduate and graduate students, including those from groups historically underrepresented in the sciences.