Cyclic RGD Peptidomimetics Containing Bifunctional Diketopiperazine Scaffolds as New Potent Integrin Ligands
Articolo
Data di Pubblicazione:
2012
Citazione:
Cyclic RGD Peptidomimetics Containing Bifunctional Diketopiperazine
Scaffolds as New Potent Integrin Ligands / M. Marchini, M. Mingozzi, R. Colombo, I. Guzzetti, L. Belvisi, F. Vasile, D. Potenza, U. Piarulli, D. Arosio, C.M.A. Gennari. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - 18:20(2012 May), pp. 6195-6207. [10.1002/chem.201200457]
Abstract:
The synthesis of eight bifunctional
diketopiperazine (DKP) scaffolds
is described; these were formally
derived from 2,3-diaminopropionic
acid and aspartic acid (DKP-1–DKP-7)
or glutamic acid (DKP-8) and feature
an amine and a carboxylic acid functional group. The scaffolds differ in the configuration at the two stereocenters and the substitution at the diketopiperazinic nitrogen atoms. The bifunctional diketopiperazines were introduced into eight cyclic peptidomimetics containing the Arg-Gly-Asp (RGD) sequence. The resulting RGD peptidomimetics were screened for their ability to inhibit biotinylated vitronectin binding to the purified integrins alphavbeta3 and alphavbeta5,
which are involved in tumor angiogenesis. Nanomolar IC50 values were obtained for the RGD peptidomimetics derived from trans DKP scaffolds (DKP-2–DKP-8). Conformational
studies of the cyclic RGD peptidomimetics by 1H NMR spectroscopy experiments (VT-NMR and NOESY
spectroscopy) in aqueous solution and
Monte Carlo/Stochastic Dynamics (MC/SD) simulations revealed that the highest affinity ligands display well-defined
preferred conformations featuring
intramolecular hydrogen-bonded
turn motifs and an extended arrangement
of the RGD sequence [Cbeta(Arg)-Cbeta(Asp) average distance > 8.8 A].
Docking studies were performed, starting
from the representative conformations
obtained from the MC/SD simulations
and taking as a reference model the crystal structure of the extracellular
segment of integrin alphavbeta3 complexed with the cyclic pentapeptide, Cilengitide. The highest affinity ligands produced top-ranked poses conserving all the important interactions of the X-ray complex.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
conformation analysis; diketopiperazines; molecular modeling; peptides; peptidomimetics
Elenco autori:
M. Marchini, M. Mingozzi, R. Colombo, I. Guzzetti, L. Belvisi, F. Vasile, D. Potenza, U. Piarulli, D. Arosio, C.M.A. Gennari
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