Chemical Tools for Protein Glycoengineering

总结 糖蛋白约占批准用于临床的所有治疗性蛋白质的70 在美国尽管有各种技术可以制造 同质材料，即使是最成功的策略也不能只产生一种（少数几种） 糖型这种局限性是一个重大挑战，可能会影响疗效、安全性和治疗效果。 生产成本。在这个项目中，我们将开发一种广泛适用的技术， 消除了与体内和离体糖蛋白产生相关的固有限制 系统.在目标1中，我们将发明并优化一种化学生物缀合反应， 提供在Asn残基处含有天然聚糖键的糖蛋白作为单个 糖型在目标2中，我们将（a）在小分子的多样化中测试新的糖缀合方法， 蛋白质和（B）证明其在含有高甘露糖的模型系统中的普遍性 聚糖总的来说，新技术将消除安全，监管和知识产权问题 目前与糖蛋白生产、操作和表征相关。

SUMMARY Glycoproteins constitute approximately 70% of all therapeutic proteins approved for clinical use in the United States. Although there are various technologies available to manufacture homogenous materials, even the most successful strategies fail to produce only one (of a few) glycoform. This limitation represents a major challenge that can affect efficacy, safety, and the costs of production. In this project, we will develop a broadly applicable technology that can eliminate the inherent limitations associated with in vivo and ex vivo glycoprotein production systems. In aim 1, we will invent and optimize a chemical bioconjugation reaction that will furnish glycoproteins containing the native glycan linkage at the Asn residue as a single glycoform. In aim 2, we will (a) test the new glycoconjugation method in diversification of small proteins and (b) demonstrate its generality in a model system containing high-mannose glycans. Taken together, the new technology will eliminate the safety, regulatory, and IP issues currently associated with glycoprotein production, manipulation, and characterization.