α_vβ₃ Integrin-Targeting Arg-Gly-Asp (RGD) Peptidomimetics Containing Oligoethylene Glycol (OEG) Spacers

Abstract

RGD peptides are used in biomaterials science for surface modifications with a view to elicit selective cellular responses. Our objective is to replace peptides by small peptidomimetics acting similarly. We designed novel molecules targeting R v β 3 integrin and featuring spacer-arms (for surface grafting), which do not disturb the biological activity, from (L) N-(3-(trifluoromethyl)benzenesulfonyl) tyrosine used as scaffold. Various Arg-mimics were fixed on the phenol function, and the ortho position was used for the coupling of OEG spacers. All peptidomimetics were active in the nM range in a binding test toward human R v β 3 integrin (IC 50 = 0.1 to 1.7 nM) and selective versus platelet integrin R IIb β 3 . Selected compounds revealed excellent ability to inhibit bone cells adhesion on vitronectin. Modeling and docking studies were performed for comparing the most active RGD peptidomimetic to cilengitide, i.e., cyclo-[RGDfN(Me)V]-. Lastly, the adhesion of endothelial cells on a cultivation support grafted with RGD peptidomimetics was significantly improved.

Tetrathiatriarylmethyl Radicals Conjugated to an RGD‐Peptidomimetic

“…Guided by the X‐ray structure17 of the extracellular part of α v β 3 integrin in complex with Cilengitide, our group has previously designed RGD‐peptidomimetics based on the L ‐tyrosine scaffold (Figure 2). The parent compound (i.e., 1 ) showed an excellent ability to bind isolated human α v β 3 integrin, with an IC 50 value of 0.1 n M 18. The derivatives (i.e., 2 ) equipped with oligoethylene glycol (OEG) spacer arms retained the antagonist activity (IC 50 = 0.3–0.7 n M ) 18.…”

“…The parent compound (i.e., 1 ) showed an excellent ability to bind isolated human α v β 3 integrin, with an IC 50 value of 0.1 n M 18. The derivatives (i.e., 2 ) equipped with oligoethylene glycol (OEG) spacer arms retained the antagonist activity (IC 50 = 0.3–0.7 n M ) 18. Moreover, the anchorage of 2 onto the surface of culture substrates allowed a strong adhesion of human endothelial cells and their retention under shear stress 19…”

RAM, an RGDS Analog, Exerts Potent Anti-Melanoma Effects In Vitro and In Vivo

“…Similarly, disintegrins molecules containing the RGD motif are known to block FGF-2-induced angiogenesis and B16F10 melanoma lung metastasis development in mice [4]. For the same reasons, molecules containing RGD motif immobilized onto appropriate matrices have pro-adhesive effects and RGD analogs may then elicit selective cellular responses such as wound healing, cell adhesion and migration [5], [6], [7]. Adhesive properties of RGD motif are been exploited for tumor imaging, targeting and radio treatment [8], [9], [10], [11], [12].…”

Self-calibrating viscosity probes: Design and subcellular localization

“…Commercially available 2-[2-(2-chloro-ethoxy)ethoxy]ethanol ( 2 ) was converted to azide 3 upon treatment with sodium azide in DMF. 24 Reduction of 3 using Pd/C as catalyst formed amine 4 , 25 which was subsequently protected to yield 5 26 in 85% yield after two steps. Esterification of alcohol 5 with cyanoacetic acid ( 6 ) produced the hydrophilic linker 7 in 78% overall yield.…”