Medicinal Chemistry of Glucagon-Like Peptide Receptor Agonists

Glucagon‐Like Peptide‐1 (GLP‐1)‐Based Therapeutics: Current Status and Future Opportunities beyond Type 2 Diabetes

“…[11] Analysis of GLP-1 using 2D-NMR revealed that the first seven amino acid residues (7-13)a tt he N-terminusf orm ar andom coil structure,w hich is thought to be responsible for interactions with the main bindingp ortion of the GLP-1R ( Figure 2). [12] This is followed by ah elical region (14)(15)(16)(17)(18)(19)(20), al inker region (21)(22)(23) and as econd helical region (24-35) ( Figure 2). [12] Alanine scanningo fe ach GLP-1 residue further revealed that residues 7, 10, 12, 13, 15, 28 and 29 ( Figure 2) are important for binding to, and activation of the GLP-1R, with mutations at these positions reducing GLP-1Ra ffinity by 132-425-fold and potency by 12-3900-fold.…”

“…[13a] Substitution of His7 with alanine resultsi nag reater than 100-fold decrease in GLP-1R affinity,a sd oes its deletion. [14] Further,a cylation of the N-terminus leads to a5 -fold decrease in binding affinity,b ut does not affect potency, [14] while N-terminal extensions result in GLP-1 analogs with limited activity.F or example, GLP-1(1-36)-NH 2 is 100-fold less potent than GLP-1(7-36)-NH 2 . [13a] In addition, His7 stereochemistry is also important for example, dhistidinesubstitutions ignificantly decreases GLP-1Rb inding affinity by 25-folda nd potencyb y3 4%.…”

“…[13a] In addition, His7 stereochemistry is also important for example, dhistidinesubstitutions ignificantly decreases GLP-1Rb inding affinity by 25-folda nd potencyb y3 4%. [14] It has thus been concluded that afree N-terminal amine, and an appropriately positioned His7 imidazole side chain are of significant importance for interactions with the GLP-1R. [14] The C-terminus of GLP-1 is also important for its activity,a lthought oalesser degree than the N-terminal histidine.…”

“…[14] It has thus been concluded that afree N-terminal amine, and an appropriately positioned His7 imidazole side chain are of significant importance for interactions with the GLP-1R. [14] The C-terminus of GLP-1 is also important for its activity,a lthought oalesser degree than the N-terminal histidine. [13a] Sequentiald eletion of amino acids 36 and 35 from the C-terminus yielded compounds with decreased GLP-1R affinity and potency, with further deletions resultingi nn ob iological activity.…”

Discovery of Antitumor Active Peptides Derived from Peroxiredoxin 5

“…Using naturally occurring hormones and other known signaling molecules as starting points is the traditional approach to lead peptide discovery, such as the development of natural intestinal incretin hormone glucagon-like peptide 1 (GLP-1). [6] With the development of technology, de novo peptides discovery has been done by screening large libraries of peptides, produced either synthetically or biologically including phage, ribosomal, and mRNA display. [1a] Additionally, numbers of modification methods have been designed and utilized to enhance the potency and pharmacokinetic profiles of peptides for clinical development.…”