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

Glucagon-like peptide-1 GLP-1 is a gut-derived peptide secreted from pancreatic β-cells that reduces blood glucose levels and body weight; however, native GLP-1 (GLP-1(7–36)-NH2 and GLP-1(7–37)) have short in vivo circulation half-lives (∼2 min) due to proteolytic degradation and rapid renal clearan...

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Bibliographic Details
Published in:Bioconjugate chemistry 2021-04, Vol.32 (4), p.810-820
Main Authors: Alavi, Seyed Ebrahim, Cabot, Peter J, Raza, Aun, Moyle, Peter M
Format: Article
Language:English
Subjects:
Alkynes
Beta cells
Biocompatibility
Biological activity
Body weight
Copper
Cycloaddition
Fibrils
Glucagon
Glucagon-like peptide 1
Lipids
Low molecular weights
Molecular weight
Nanofibers
Pancreas
Parameter modification
Peptides
Pharmacokinetics
Proteolysis
Self-assembly
Stability
Toxicity
Transmission electron microscopy
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Summary:Glucagon-like peptide-1 GLP-1 is a gut-derived peptide secreted from pancreatic β-cells that reduces blood glucose levels and body weight; however, native GLP-1 (GLP-1(7–36)-NH2 and GLP-1(7–37)) have short in vivo circulation half-lives (∼2 min) due to proteolytic degradation and rapid renal clearance due to its low molecular weight (MW; 3297.7 Da). This study aimed to improve the proteolytic stability and delivery properties of glucagon-like peptide-1 (GLP-1) through modifications that form nanostructures. For this purpose, N- (NtG) and C-terminal (CtG), and Lys26 side chain (K26G) alkyne-modified GLP-1 analogues were conjugated to an azide-modified lipidic peptide (L) to give N-L, C-L, and K-26-L, respectively; or CtG was conjugated with a fibrilizing self-assembling peptide (SAP) (AEA­EA­KAK)3 to yield C-S, using copper­(I)-catalyzed azide–alkyne cycloaddition (CuAAC). N-L demonstrated the best serum stability (t 1/2 > 48 h) compared to K-26-L (44 h), C-L (20 h), C-S (27 h), and the parental GLP-1­(7–36;A8G)-NH2 (A8G) (19 h) peptides. Each conjugate demonstrated subnanomolar hGLP-1RA potency, and none demonstrated toxicity toward PC-3 cells at concentrations up to 1 μM. Each analogue was observed by transmission electron microscopy to form fibrils in solution. K-26-L demonstrated among the best human serum stability (t 1/2 = 44 h) and similar hGLP-1RA potency (EC50 48 pM) to C-S. In conclusion, this study provided an alternative to lipid modification, i.e., fibrillizing peptides, that could improve pharmacokinetic parameters of GLP-1.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.1c00091