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Glycoengineering of Therapeutic Peptides for Improved Treatment of Human Diseases

用于改善人类疾病治疗的治疗性肽的糖工程

基本信息

批准号：
9977199
负责人：
TAREK SAMMAKIA
金额：
$ 33.36万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977199
关键词：
Address Affect Agonist Amino Acid Sequence Animals Attention Biochemistry Biological Biological Availability Biological Products Biophysics Calcitonin Cellular biology Chemicals Chronic Chronic Disease Collection Communicable Diseases Complex Dangerousness Data Development Diabetes Mellitus Disadvantaged Dose Engineering Environment Frequencies GLP-I receptor Goals Guidelines Human Inflammatory Influentials Injections Insulin Lead Libraries Link Malignant Neoplasms Metabolic Diseases Methods Modeling Modification Molecular Conformation Nature Non-Insulin-Dependent Diabetes Mellitus Oral Pain Patients Pattern Peptide Hydrolases Peptides Performance Pharmaceutical Preparations Polymers Polysaccharides Preparation Process Property Protein Glycosylation Research Resistance Route Site Small Intestines Specificity Stomach Stress Structure Subcutaneous Injections T-20 Techniques Technology Testing Therapeutic Time Variant Work absorption base chemical synthesis compliance behavior crosslink design diabetic disulfide bond exenatide flexibility glucagon-like peptide 1 glycosylated insulin glycosylation human disease improved liraglutide novel therapeutics peptide drug peptide structure physical property polymerization side effect small molecule sugar teduglutide tool

项目摘要

Project Summary Peptides are now widely used to treat human diseases and represent a fast-growing class of therapeutics in the biopharmaceutical market. In general, peptides have the advantages of high specificity and potency but the disadvantages of being susceptible to aggregation and proteolytic degradation. Because of these drawbacks, therapeutic peptides are often administered through injections and, in order to maintain sufficient levels of circulating biologically active peptides, such injections are often frequent. This makes the treatment process expensive, inconvenient, and occasionally dangerous to patients, particularly during long-term treatment of chronic diseases. To address these issues, many attempts have been made to develop less invasive routes for peptide administration. By selectively retarding drug release in the acidic environment of the stomach through the use of pH sensitive polymers, peptides can now be efficiently conveyed to the small intestine, where the majority of drug absorption occurs after oral delivery. The absorption of peptides in the small intestine is not, however, free of challenges. For example, self-association and degradation by proteases located in the small intestinal lumen can significantly lower the bioavailability of peptides. Recently, we have demonstrated that almost all of the relevant physical properties of peptides can be altered by attaching particular glycans to flexible or fragile regions. Based on these results, we hypothesize that better guidelines of using glycans in peptide engineering can be developed by deeply examining the effects of glycosylation on two representative therapeutic peptides: human insulin and glucagon-like peptide-1 (GLP-1). The objective of our proposed research is to test this hypothesis through chemical synthesis and biological characterization of collections of differently O-glycosylated insulin and GLP-1 variants. We will begin our study by investigating how O-linked glycans modulate various properties of insulin. This will be achieved by designing, quantifying and then comparing the properties of a library of synthetically prepared, pure, and homogeneous insulin glycoforms with systematic variations in glycosylation patterns (glycosylation sites, glycan sizes and structures) and/or amino acid sequences. In the second part of the study, we will use a similar strategy to evaluate the effects of O-glycosylation on the properties of GLP-1. The proposed study is one of the first attempts to develop a rational approach to glycoengineer therapeutic peptides with a focus on O-glycosylation. The results of the proposed research are expected to lead to a better understanding of peptide glycoengineering, O-glycosylation, and facilitate the development of novel therapeutic peptides for the treatment of human diseases.

项目总结