Peptide Oligomerization Memory Effects and Their Impact on the Physical Stability of the GLP-1 Agonist Liraglutide

Abstract

Peptides and proteins commonly have complex structural landscapes allowing for transformation into a wide array of species including oligomers, aggregates, and fibrils. The formation of undesirable forms including aggregates and fibrils poses serious risks from the perspective of drug development and disease. Liraglutide, a GLP-1 agonist for the treatment of diabetes, is a conjugated peptide that forms oligomers that can be stabilized by pH and organic solvents. We have developed an analytical toolkit to overcome challenges inherent to Liraglutide’s conjugated acyl chain and probed the impact its oligomers have on its physical stability. Our studies show that Liraglutide’s oligomer states have significant and potentially detrimental impacts on its propensity to aggregate and form fibrils as well as its potency. Liraglutide delivered as a synthetic peptide is able to maintain its oligomerization state in dried lyophilized powders, acting as a memory effect from its synthetic process and purification. Through Liraglutide’s oligomer memory effect, we demonstrate the importance and impact the process for synthetic peptides can have on drug development spanning from discovery to formulation development.

Developing GLP-1 Conjugated Self-Assembling Nanofibers Using Copper-Catalyzed Alkyne–Azide Cycloaddition and Evaluation of Their Biological Activity

“…Because of these benefits, lipid modifications of GLP-1 analogues have been reported. Backing up the findings herein, Liraglutide (Victoza), a GLP-1­(7–37;K34R) peptide, incorporating a different lipid moiety (palmitic acid conjugated to Lys26 through a glutamate linker), has also been demonstrated to form fibrils in solution …”

“…Backing up the findings herein, Liraglutide (Victoza), a GLP-1(7−37;K34R) peptide, incorporating a different lipid moiety (palmitic acid conjugated to Lys26 through a glutamate linker), has also been demonstrated to form fibrils in solution. 37 In addition, the nanostructures formed by C-S and S were assessed by TEM (Figure 4). The results demonstrated that both S and C-S individually aggregated and formed nanofibrils, which further aggregated to yield nanofibers of approximately 200 nm width (Figure 4).…”

A Model Study to Assess Fibrillation and Product Stability to Support Peptide Drug Design

“…16,18,19 Early molecular events such as conformational changes and oligomer formation can predispose peptides to fibrillation later. 20 Detection of these early instabilities through additional biophysical methods may inform formulation optimization, accelerate the selection of fibrillation-resistant peptide candidates and formulations, and reduce the risk of costly late-stage failures.…”

A review of recent research and development on GLP-1 receptor agonists-sustained-release microspheres

“…50,51 At present, there are still some difficulties and challenges in the preparation and application of GLP-1 RA-loaded microspheres. For example, GLP-1 RAs are sensitive to changes in the pH environment, which may lead to aggregation and fibrillation, 52,53 and at the same time, their peptide aminebased structure is prone to acylation reactions with polymer materials causing immunogenicity. So the stability and safety of the peptide after being encapsulated need more attention.…”