Helixconstraints and amino acid substitution in GLP-1 increase cAMP and insulin secretion but not beta-arrestin 2 signaling.
Eur J Med Chem
; 127: 703-714, 2017 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-27823886
ABSTRACT
Glucagon-like peptide (GLP-1) is an endogenous hormone that induces insulin secretion from pancreatic islets and modified forms are used to treat diabetes mellitus type 2. Understanding how GLP-1 interacts with its receptor (GLP-1R) can potentially lead to more effective drugs. Modeling and NMR studies of the N-terminus of GLP-1 suggest a ß-turn between residues Glu9-Phe12 and a kinked alpha helix between Val16-Gly37. N-terminal turn constraints attenuated binding affinity and activity (compounds 1-8). Lys-Asp (i, i+4) crosslinks in the middle and at the C-terminus increased alpha helicity and cAMP stimulation without much effect on binding affinity or beta-arrestin 2 recruitment (compounds 9-18). Strategic positioning of helix-inducing constraints and amino acid substitutions (Tyr16, Ala22) increased peptide helicity and produced ten-fold higher cAMP potency (compounds 19-28) over GLP-1(7-37)-NH2. The most potent cAMP activator (compound 23) was also the most potent inducer of insulin secretion.
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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AMP Cíclico
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Substituição de Aminoácidos
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Peptídeo 1 Semelhante ao Glucagon
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Beta-Arrestina 2
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Insulina
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article