Chemical Tools for Protein Glycoengineering

摘要 糖蛋白约占所有获准临床使用的治疗蛋白的70%。 在美国。尽管有各种技术可以用来制造 同质材料，即使是最成功的策略也无法产生(少数几种)中的一种 糖型。这一限制是一个重大挑战，可能会影响疗效、安全性和 生产成本。在这个项目中，我们将开发一种广泛适用的技术，可以 消除与体内和体外糖蛋白生产相关的固有限制 系统。在目标1中，我们将发明和优化一种化学生物偶联反应，它将 在ASN残基上提供含有天然糖链的糖蛋白作为单一的 糖型。在目标2中，我们将(A)测试新的糖偶联法在小鼠 蛋白质和(B)在含有高甘露糖的模型系统中展示了它的一般性 多聚糖。总而言之，新技术将消除安全、监管和IP问题 目前与糖蛋白的生产、操作和特性有关。

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.