Non-Peptide RGD Surrogates Which Mimic a Gly-Asp β-Turn:  Potent Antagonists of Platelet Glycoprotein IIb−IIIa

Abstract

Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet receptor GPIIb-IIIa and was chosen for study by 1H NMR techniques. The key RGD sequence of this molecule was found to reside in a conformationally defined type II' Gly-Asp beta-turn, and this information was used in the design of simple non-peptide RGD mimics. Disubstituted isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6, were prepared and were found to have modest affinity for GPIIb-IIIa. Systematic modification of the basic residue contained in these molecules yielded compounds with high affinity for GPIIb-IIIa.

Self-assembled nanoparticles based on the c(RGDfk) peptide for the delivery of siRNA targeting the VEGFR2 gene for tumor therapy

“…4 Additionally, these carriers have been modified with different targeting ligands, such as the Arg-Glytargeting ability. The RGD peptide and structurally related compounds [9][10][11][12][13][14] are the best-studied ligands that belong to the integrin ligand group. [15][16][17][18] Because these ligands specifically bind to the integrin receptor, which is overexpressed in the endothelial cells of the tumor neovasculature, 19 when applied in vivo, an 8-amino-3,6-dioxaoctanoic acid (PEG)-β-maleimidopropionic acid (MAL) hydrophilically modified, specific integrin αvβ3 receptor-targeted small cyclopeptide c(RGDfk) could lead to the accumulation of siRNA in tumors, resulting in tumor targeting.…”

Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats

“…[16][17][18][19] The most studied integrin ligands have been the Arg-Gly-Asp (RGD) motif and structurally related compounds. [20][21][22][23][24][25] The RGD motif can be specifically recognized by integrins α ν β 3 and α ν β 5 which are overexpressed on many solid tumors and in tumor neovasculature, such as in human glioma. 26 Thus, modification of SSL with the RGD motif to achieve targeted drug delivery to tumors and the tumor neovasculature is a promising strategy in the treatment of glioma.…”

Utilizing Peptide Structures As Keys For Unlocking Challenging Targets

“…Using the NMR-derived structure as a guide, they designed inhibitors using an oxoisoquinoline scaffold. Binding affinities in the nM range were ultimately achieved [57].…”