Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds

Abstract

Integrin ligands containing the tripeptide sequences Arg-Gly-Asp (RGD) and iso-Asp-Gly- Arg (isoDGR) were actively investigated as inhibitors of tumor angiogenesis and directing unit in tumor-targeting drug conjugates. Reported herein is the synthesis, of two RGD and one isoDGR cyclic peptidomimetics containing (1S,2R) and (1R,2S) cis-2-amino-1-cyclopentanecarboxylic acid (cis-β-ACPC), using a mixed solid phase/solution phase synthetic protocol. The three ligands were examined in vitro in competitive binding assays to the purified αvβ3 and α5β1 receptors using biotinylated vitronectin (αvβ3) and fibronectin (α5β1) as natural displaced ligands. The IC50 values of the ligands ranged from nanomolar (the two RGD ligands) to micromolar (the isoDGR ligand) with a pronounced selectivity for αvβ3 over α5β1. In vitro cell adhesion assays were also performed using the human skin melanoma cell line WM115 (rich in integrin αvβ3). The two RGD ligands showed IC50 values in the same micromolar range as the reference compound (cyclo[RGDfV]), while for the isoDGR derivative an IC50 value could not be measured for the cell adhesion assay. A conformational analysis of the free RGD and isoDGR ligands by NMR (VT-NMR and NOESY experiments) and computational studies (MC/EM and MD), followed by docking simulations performed in the αVβ3 integrin active site, provided a rationale for the behavior of these ligands toward the receptor.

Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand

“…This would suggest that the dual inhibition of these RGD integrins can be a promising strategy to develop brand-new anti-HSV therapeutic agents. Nonetheless, while many ligands are available for αIIbβ3, αvβ3, and α5β1, − few selective binders are known for αvβ6 and αvβ8. − In this regard, we recently identified a cyclic pentapeptide, namely, [RGD-Chg-E]-CONH 2 ( 1 ) (Chart ), as a potent and preferential αvβ6 ligand, which was successfully converted into an effective probe for molecular imaging . Considering that herpesviruses employ both αvβ6 and αvβ8 as co-receptors for cellular entry, a dual ligand of these integrins should represent a more efficient anti-HSV agent than the corresponding mono-αvβ6- or αvβ8-selective binders.…”

nature inspired and medicinally relevant short peptides

“…The unraveling of the bioactive conformation of cilengitide bound to integrin αVβ3 [222] and the rationalization of the biological affinity provided by Kessler's studies inspired and guided rational designs of several peptidomimetic ligands [222][223][224][225], including some integrin inhibitors which entered to clinical phases [221]. In the pioneering work of Mas-Moruno et al [226], a systematic stepwise strategy was developed to design cyclic peptides under "conformational control".…”

Nature-inspired and medicinally relevant short peptides

“…The unraveling of the bioactive conformation of cilengitide bound to integrin αVβ3 [222] and the rationalization of the biological affinity provided by Kessler's studies inspired and guided rational designs of several peptidomimetic ligands [222][223][224][225], including some integrin inhibitors which entered to clinical phases [221]. In the pioneering work of Mas-Moruno et al [226], a systematic stepwise strategy was developed to design cyclic peptides under "conformational control".…”