Transferrin Fusion Technology: A Novel Approach to Prolonging Biological Half-Life of Insulinotropic Peptides

Abstract

Fusion proteins made up of glucagon-like peptide 1 (GLP-1) and exendin-4 (EX-4) fused to a nonglycosylated form of human transferrin (GLP-1-Tf or EX-4-Tf) were produced and characterized. GLP-1-Tf activated the GLP-1 receptor, was resistant to inactivation by peptidases, and had a half-life of approximately 2 days, compared with 1 to 2 min for native GLP-1. GLP-1-Tf retained the acute, glucose-dependent insulin-secretory properties of native GLP-1 in diabetic animals and had a profound effect on proliferation of pancreatic ␤-cells. In addition, Tf and the fusion proteins did not cross the blood-brain-barrier but still reduced food intake after peripheral administration. EX-4-Tf proved to be as effective as EX-4 but had longer lived effects on blood glucose and food intake. This novel transferrin fusion technology could improve the pharmacology of various peptides.

Euglycemic Agent-mediated Hypothalamic Transcriptomic Manipulation in the N171–82Q Model of Huntington Disease Is Related to Their Physiological Efficacy

“…3E). These findings corroborate previous findings on the effects of these compounds on glycemic hormone levels in WT animals (9,17). In contrast, both Ex-4 and GLP-1-Tf treatments significantly lowered blood glucose levels in HD mice (Fig.…”

“…4, A-F). Ex-4 and GLP-1-Tf are effective treatments for type 2 diabetes, as they not only protect pancreatic beta-cell function but also significantly improve insulin sensitivity (9,17,20). Insulin treatment did not alter islet size and beta-cell numbers in HD mice (Fig.…”

“…As the hypothalamus may represent an important therapeutic locus in HD, we have investigated hypothalamic transcriptional changes in the N171-82Q HD mouse model induced by three functionally related euglycemic agents. These agents are structurally distinct pharmacological compounds that possess convergent euglycemic mechanisms as follows: insulin (Lantus), Ex-4, and a novel long acting GLP-1 receptor agonist GLP-1-Tf (17). Ex-4, but not GLP-1-Tf, can enter the brain (17).…”

“…These agents are structurally distinct pharmacological compounds that possess convergent euglycemic mechanisms as follows: insulin (Lantus), Ex-4, and a novel long acting GLP-1 receptor agonist GLP-1-Tf (17). Ex-4, but not GLP-1-Tf, can enter the brain (17). As recent research has demonstrated HD to be a more multidimensional disorder than previously thought, encompassing neurodegeneration, protein aggregation, and metabolic disruption, we decided to develop a methodology that could appreciate, at a multifactorial level, the likely multitude of therapeutic mechanisms that could combine to ameliorate the complex HD pathophysiology.…”

Chemical and Genetic Modification

“…Recently, human growth hormone-Tf fusion was evaluated in preclinical studies [240]. Tf fusion technology has also been applied to GLP-1 and exendin-4 (EX-4) in efforts to improve their pharmacology [241].…”