Influence of Selective Fluorination on the Biological Activity and Proteolytic Stability of Glucagon-like Peptide-1

Abstract

The relative simplicity and high specificity of peptide therapeutics has fueled recent interest. However, peptide and protein drugs generally require injection and suffer from low metabolic stability. We report here the design, synthesis and characterization of fluorinated analogues of the gut hormone peptide, GLP-1. Overall, fluorinated GLP-1 analogues displayed higher proteolytic stability with simultaneous retention of biological activity (efficacy). Fluorinated amino acids are useful for engineering peptide drug candidates and probing ligand-receptor interactions.

A new paradigm for protein design and biological self-assembly

“…However, the use of native GLP-1 in clinical settings is limited because it is rapidly (~2 mins) degraded by the serine protease DPP IV [34]. The greater membrane affinity and structural stability of fluorinated peptides prompted us to design analogues of GLP-1 containing hexafluoroleucine [35]. Sites were chosen such that they would have the greatest effect on binding to its cognate receptor (GLP-1R) or in protection from protease catalyzed cleavage (Figure 3).…”

Biosynthetic Incorporation of Fluorinated Amino Acids into Peptides and Proteins

“…The introduction of fluorine also increases the resistance of peptides to thermal and chemical denaturation, [20,[40][41][42][43] oxidation, [44] and proteolysis. [45,46] Fluorinated amino acids can also be used to manipulate hydrophobicity [47] and local electronic environments, [36,48] as well as alter the reactivity of catalytic groups. [49,50] For example, the kinetics of an isomerase enzyme have been modified by replacing the active site, catalytic tyrosine with fluorinated analogues having altered acidities.…”

Medicinal Chemistry of Glucagon-Like Peptide Receptor Agonists

“…Nevertheless, Kumar and co-workers have described the incorporation of hexafluoroleucine at specific sites in the GLP-1 molecule to specifically block proteolytic cleavage by DPP-IV [47]. Nevertheless, Kumar and co-workers have described the incorporation of hexafluoroleucine at specific sites in the GLP-1 molecule to specifically block proteolytic cleavage by DPP-IV [47].…”