Targeting integrins: Insights into structure and activity of cyclic RGD pentapeptide mimics containing azabicycloalkane amino acids

N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin

“…Gal-3 was prepared by recombinant production and purified using affinity chromatography and checked for purity by one-and two-dimensional gel electrophoresis and mass spectrometry (32). To exclude the possibility that Ac-SDKP binds Gal-3 and directly interferes with its effects, we performed binding assays with biotinylated Gal-3, both in solid phase (with asialofetuin as matrix) (2) and in a cell system with the natural glycan profile (5). Biotinylated Gal-3 was quantitated spectrophotometrically or by flow cytometry, in the presence of lactose (a positive control) or Ac-SDKP.…”

A Potent Integrin Antagonist from a Small Library of Cyclic RGD Pentapeptide Mimics Including Benzyl‐Substituted Azabicycloalkane Amino Acids

“…Previously, cyclic pseudopeptides have been prepared by solid-phase synthesis. [18,19] However, the use of large quantities of resins was shown to be troublesome and expensive, precluding the application of this methodology to large scale production. A solution phase method was therefore adopted.…”

“…The minimum-energy conformations of these cyclic pentapeptide mimics are characterized by the formation of peptide secondary structures, in particular band g-turns, that may be stabilized by intramolecular hydrogen bonds. As shown in Table 2, the same four significant geometries (types SI-SIV) calculated for ligands of the general formula 2 [19] can be detected among the conformers within 3 kcal mol…”

“…[18] The replacement of the d-Phe-Val dipeptide in the lead structure cycloA C H T U N G T R E N N U N G (RGDfV) with such azabicycloalkane scaffolds, inducing different conformational preferences of the RGD sequence, provide the required activity and selectivity for integrin antagonism. [19] This library was found to contain specific high-affinity ligands for a V b 3 and a V b 5 integrins, which are presently being evaluated as very promising antiangiogenic drugs. Among the peptides tested, 3 (ST1646) showed the highest affinity to a V b 3 and a high affinity to a V b 5 , inhibiting echistatin binding to a V b 3 and a V b 5 with an IC 50 value of 3.7 AE 0.6 nm and 1.39 AE 0.2 nm, respectively.…”

“…Among the peptides tested, 3 (ST1646) showed the highest affinity to a V b 3 and a high affinity to a V b 5 , inhibiting echistatin binding to a V b 3 and a V b 5 with an IC 50 value of 3.7 AE 0.6 nm and 1.39 AE 0.2 nm, respectively. [18][19][20] To further address the process of spatial screening, the original library was expanded to include new members, modified at the scaffold moiety either by introducing a hydrophobic substituent or enlarging the lactam ring. [21] A preliminary work in this direction led to compound 4 showing affinity and selectivity towards the a v b 5 integrin receptor with an IC 50 value of 4.12 AE 1.1 nm.…”