Si trova su / Altri legami
© 2021 American Chemical Society.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 (t1/2 > 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 (t1/2 = 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.
