Structural requirements of the N-terminal region of GLP-1-[7-37]-NH2 for receptor interaction and cAMP production.
A series of GLP-1-[7-36]-NH(2) (tGLP-1) and GLP-1-[7-37] analogs modified in position 7, 8, 9 and 36, have been designed and evaluated on murine GLP-1 receptors expressed in RIN T3 cells for both their affinity and activity. Ten of the synthesized peptides were found full agonists with activities superior or at least equal to that of the native hormone. Five of them were investigated for their plasmatic stability and the most stable, [a(8)-desR(36)]GLP-1-[7-37]- NH(2) (Compound 8), evaluated in vivo in a glucose tolerance test which confirmed a clearly longer activity than that of the native hormone. We also performed circular dichroism study and propose a hypothetical structural model explaining the most part of observed activities of GLP-1 analogs on RIN T3 cells.
Sarrauste de Menthière
Cyril
C
Centre de Biochimie Structurale, CNRS UMR 5048 - UM1 - INSERM UMR 554, 29 rue de Navacelles, 34090 Montpellier Cedex, France.
Chavanieu
Alain
A
Grassy
Gérard
G
Dalle
Stéphane
S
Salazar
Guillermo
G
Kervran
Alain
A
Pfeiffer
Bruno
B
Renard
Pierre
P
Delagrange
Philippe
P
Manechez
Dominique
D
Bakes
David
D
Ktorza
Alain
A
Calas
Bernard
B
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002942:Circular Dichroism; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000737:chemistry; D005768:Gastrointestinal Hormones / Q000138:chemical synthesis* / Q000378:metabolism; D005934:Glucagon / Q000138:chemical synthesis* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism; D011487:Protein Conformation; D011498:Protein Precursors / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D018027:Receptors, Glucagon / Q000378:metabolism*; D013329:Structure-Activity Relationship
D005768:Gastrointestinal Hormones; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP