Development of programmable nanomachines towards the enzymatic synthesis of peptide oligonucleotide conjugates

This fellowship will be used to establish a multidisciplinary team working at the interface of chemistry, biology and protein engineering at the University of York, UK. The overarching goal of my group's research will be to develop novel approaches for biopolymer synthesis, design and discovery. In the process, we want to unravel the mechanisms that control and modulate the behavior of enzymes and proteins. The methodologies developed and insights gained through this proposal will inform the synthesis strategies for a new generation of therapeutics and biomaterials. Chemical synthesis remains the mainstay for the production of drugs, including the modern, next generation biologics composed of peptides, proteins, DNA, RNA, carbohydrates and their conjugates. Biomolecular conjugates have also found use as nanomaterials, drug delivery vehicles and components of biocomputers. Traditional chemical methods of synthesis require harsh conditions such as high temperature, non-aqueous solvents and non-physiological pH - parameters that are often incompatible with the manufacture of biomolecules. It is therefore imperative that alternative, sustainable strategies are explored. Enzymes present a biocompatible mode of synthesis that is starting to be exploited for the manufacture of biomolecular drugs. In this proposal, my research group will focus on adapting natural enzymes to perform the synthesis of a commonly used hybrid biomolecule - peptide-oligonucleotide conjugate. The knowledge gained will be used to further expand the existing repertoire of biologics and biomaterials.