Chemical Tools for Protein Glycoengineering

蛋白质糖工程化学工具

基本信息

批准号：
10041583
负责人：
Maciej Walczak
金额：
$ 22.77万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10041583
关键词：
Acids Affect Amides Antibodies Asparagine Attention Biological Biological Models Cessation of life Chemicals Clinical Coupled Data Development Diagnostic Esters Feasibility Studies Funding Glycopeptides Glycoproteins Goals Human Resources Hydrolysis In Vitro Link Literature Mannose Methodology Methods Modeling Nature Oligosaccharides Peptides Pharmaceutical Preparations Polysaccharides Post-Translational Protein Processing Production Protein Engineering Protein Glycosylation Proteins Reaction Reagent Recombinant Proteins Recombinants Reporting Safety Shock Standardization System Technology Testing Therapeutic Training United States Vaccines base clinical practice clinically significant cost cost effective crosslink dehydroalanine improved in vivo interest new technology oxidation racemization response small molecule technology development technology research and development therapeutic protein tool

项目摘要

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.

概括糖蛋白约占批准用于临床使用的所有治疗蛋白的70％在美国。尽管有各种各样的技术可以生产同质材料，即使最成功的策略也没有生产（少数）糖型。这种限制代表了可能影响疗效，安全性和生产成本。在这个项目中，我们将开发一项广泛适用的技术，可以消除与体内和体内糖蛋白产生相关的固有局限性系统。在AIM 1中，我们将发明和优化化学生物偶联反应提供包含ASN残基的本机聚糖连接的糖蛋白作为单个糖型。在AIM 2中，我们将（a）测试新的糖缀合法以多样化蛋白质和（b）在包含高曼诺糖的模型系统中演示了其通用性聚糖。综上所述，新技术将消除安全，法规和IP问题目前与糖蛋白产生，操纵和表征有关。