Integrin α₅β₁ Ligands: Biological Evaluation and Conformational Analysis

Abstract

Breaking up is easy. Integrin α5β1 is a cell‐surface receptor involved in many physiological and pathological processes. Small cyclic peptides can influence the interaction between this receptor and its natural ligand, fibronectin. The peptide shown, c‐(‐Arg‐Gly‐Asp‐D‐Phe‐Val‐β‐Ala‐), can bind α5β1 with submicromolar affinity. A conformational analysis of the peptide provided information on the structural properties responsible for binding to α5β1.

Conformational Control of Integrin‐Subtype Selectivity in isoDGR Peptide Motifs: A Biological Switch

“…To our knowledge, this is the first reported cyclic peptide based on a retro-RGD sequence with nanomolar activity and selectivity for a5b1. Only one natural peptide (c(CRRETAWAC) [19] ) and some cyclic RGD peptides with ß-amino acids [20,21] ) have been described with similar activities and selectivities in cellular assays. Such a biological profile could help to clarify the molecular basis of the cancerinhibitory effect of Cilengitide.…”

Rationales Design von hoch aktiven und selektiven Liganden für α5β1‐ und αvβ3‐Integrine

“…[10,11] Anders als im Fall der Integrine avb3 und aIIbb3, deren aufgeklärte Kristallstrukturen detaillierte Einblicke in die Bindung von Liganden ermöglichten, [12,13] gibt es vom a5b1-Integrin nur unzureichende Daten zu Struktur und Bindungsverhalten. [14] Der Mangel an Liganden [15,16] für das a5b1-Integrin bewog uns, diesen Rezeptor näher zu untersuchen. Erste Anhaltspunkte für die Struktur neuer möglicher a5b1-Liganden lieferte das Homologiemodell des a5b1-Integrins im Komplex mit dem kürzlich publizierten Liganden SJ749.…”

The Constrained Amino Acid β‐Acc Confers Potency and Selectivity to Integrin Ligands

“…Reference peptide 2 is also characterized by an elongated conformation of the RGD sequence with a distance of 930 pm between C b atoms of Arg and Asp, which correlates well with the lower affinity toward integrin a V b 3 . [3] With incorporated b-Accs, peptides 3 and 4 contain conformationally highly restrained b-amino acids. For peptide 3, the distance between the C b atoms of Asp and Arg is 706 pm in the central structure of the major cluster.…”

“…[2] Although integrin a 5 b 1 is also involved in angiogenesis, it participates predominantly in various inflammatory disorders, for example, asthma and rheumatoid arthritis. [3] Therefore, the discovery of new peptide ligands displaying high activity and selectivity is a challenge for both biochemistry and medicinal chemistry.…”

“…Adhesion of the K562 and WM115 cells to their ligands fibronectin and vitronectin is predominantly mediated by integrins a 5 b 1 and a V b 3 , respectively. [3] The ability of the RGD peptides 3 and 4 to inhibit the adhesion of the K562 and WM115 cells to their ligands was compared with the previously described peptides cyclo-(-Arg-Gly-Asp-d-Phe-Val-) (1) [4] and cyclo-(-Arg-GlyAsp-d-Phe-Val-b-Ala-) (2) [3] as references (Table 1).…”