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

该奖学金将用于在英国约克大学建立一个多学科团队，研究化学，生物学和蛋白质工程的界面。我们小组研究的首要目标将是开发生物聚合物合成、设计和发现的新方法。在这个过程中，我们想要解开控制和调节酶和蛋白质行为的机制。通过该提案开发的方法和获得的见解将为新一代疗法和生物材料的合成策略提供信息。化学合成仍然是药物生产的主要手段，包括由多肽、蛋白质、DNA、RNA、碳水化合物及其偶联物组成的现代下一代生物制剂。生物分子偶联物也被用作纳米材料、药物输送载体和生物计算机组件。传统的化学合成方法需要苛刻的条件，如高温、非水溶剂和非生理pH参数，这些参数通常与生物分子的制造不相容。因此，必须探索其他可持续战略。酶呈现出一种生物相容性的合成模式，正开始被用于制造生物分子药物。在这个提案中，我的研究小组将专注于利用天然酶来合成一种常用的杂交生物分子-肽-寡核苷酸缀合物。所获得的知识将用于进一步扩大现有的生物制剂和生物材料。

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.