Conformations and pharmacophores of cyclic RGD containing peptides which selectively bind integrin αvβ3

Abstract

This paper reports a detailed conformational characterization in solution by 1H-NMR in H2O and DMSO-d6 and molecular modeling simulations of cyclic peptides containing the RGDDV pharmacophore and the RGDY(Me)R pharmacophore. These two pentapeptide sequences when properly constrained in cyclic peptides are low to sub-nanomolar inhibitors of integrin alpha(v)beta3. The peptides containing the RGDDY(Me)R sequence bind potently to integrin alphaIIb3 as well. The conformations found in H2O and in DMSO-d6 solutions are valuable for the design of peptidomimetics of these two pharmacophores. The structure-activity relationships of the RGDDV and RGDY(Me)R pharmacophores within cyclic peptides are discussed. Specifically, the orientation of surface-accessible chemical features on the ligand, such as hydrophobic, positive and negative ionizable groups, which are considered to be responsible for the desired biological activity, is focused on.

Effect of RGD peptide coating of titanium implants on periimplant bone formation in the alveolar crest

“…In vitro , the initial responses of human osteoblast‐like cells were mediated by α2β1‐ and αvβ3‐integrin receptors (Healy et al. 1999; Locardi et al. 1999), while αvβ3‐receptors also appeared to induce longer‐term events (Healy et al.…”

Mapping the binding domains of the αIIb subunit

“…mAbs recognizing specific epitopes on the extracellular domains of both subunits are also able to induce/stabilize conformational changes of a IIb b 3 , which increase the affinity of the receptor for its ligands [11][12][13].The discovery that the RGD sequence is present in a surprisingly large number of adhesive proteins, serving diverse functions, has led to extensive research in the development of small RGD-containing peptides as antithrombotic agents. Elucidation of the pharmacophoric nature of the Asp and Arg side-chains allowed new strategies, largely based on bioactive RGD conformations, to be developed for the rational design of peptide hybrids and nonpeptide mimetics as potential therapeutic drugs against platelet aggregation [14][15][16][17][18][19].Recently, it has been proposed that binding of the RGD peptide leads to changes in a IIb b 3 that are associated with acquisition of high-affinity fibrinogen-binding function and subsequent platelet activation, despite the initial RGDinhibitory effect [20]. Consequently, an alternative approach would be to inhibit RGD-mediated platelet activation by defining the ligand-binding sites on the receptor.…”

“…The discovery that the RGD sequence is present in a surprisingly large number of adhesive proteins, serving diverse functions, has led to extensive research in the development of small RGD-containing peptides as antithrombotic agents. Elucidation of the pharmacophoric nature of the Asp and Arg side-chains allowed new strategies, largely based on bioactive RGD conformations, to be developed for the rational design of peptide hybrids and nonpeptide mimetics as potential therapeutic drugs against platelet aggregation [14][15][16][17][18][19].…”

Interaction Mechanism and Clustering among RGD Peptides and Integrins

“…We believe that two factors, i. e., the relative orientation and distance between RGD‐containing peptides and integrin α V β 3 , influence the resulting interactions. Of these, relative orientation is the main influencing factor, as observed by other researchers . As discussed above, the guanidine of ARG is the specific site through which RGD‐containing peptides interact with integrin α V β 3 .…”

“…Of these, relative orientation is the main influencing factor, as observed by other researchers. [39] As discussed above, the guanidine of ARG is the specific site through which RGD-containing peptides interact with integrin a V b 3 . Therefore, this group must face a V b 3 to form effective interactions.…”