Die gerüststarre Aminosäure β‐Acc verleiht Integrinliganden Aktivität und Selektivität

Urman, Sylwia; Gaus, Katharina; Yang, Yi; Strijowski, Ulf; Sewald, Norbert; Pol, Silvia De; Reiser, Oliver

doi:10.1002/ange.200605248

Cited by 20 publications

(7 citation statements)

References 24 publications

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“…Unserem Wissen nach ist dies das erste cyclische Peptid basierend auf einer retro‐RGD‐Sequenz, das eine nanomolare Aktivität und Selektivität für α5β1 zeigt. Es gibt lediglich das natürliche Peptid c (CRRETAWAC)19 und cyclische RGD‐Peptide mit β‐Aminosäuren,20, 21 für die in Zellstudien ähnlich gute Aktivitäten und Selektivitäten gezeigt wurden. Dieses biologische Profil kann zur Aufklärung der molekularen Wirkungsweise von Cilengitid beitragen.…”

Section: Methodsunclassified

Konformative Kontrolle über Integrin‐Subtyp‐Selektivitäten in isoDGR‐Peptidmotiven: ein biologischer Schalter

et al. 2010

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Section: Methodsunclassified

Konformative Kontrolle über Integrin‐Subtyp‐Selektivitäten in isoDGR‐Peptidmotiven: ein biologischer Schalter

et al. 2010

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“…Later, the same group reported the synthesis, structural analysis and biological evaluation of pentapeptides containing the constrained cis-βaminocyclopropanecarboxylic acid (β-Acc). [89] The cyclic pentapeptide c(RGD-(+)-β-Acc-V) (Table 1) exhibited a very high activity for αvβ3 (20 nM) in a cellular adhesion assay of WM115 cells to FN and good selectivity against α5β1 (1.5 µM, 75-fold) of K562 cells on FN. In 2008, Pramanik et al reported that a lipopeptide with the tetrapeptide sequence RGDK could selectively target genes to the α5β1 integrin receptor in vitro.…”

Section: N-methylation Of C(rgdfv) Led To the Drug Candidate Cilengitmentioning

confidence: 99%

αvβ3‐ or α5β1‐Integrin‐Selective Peptidomimetics for Surface Coating

et al. 2016

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Engineering biomaterials with integrin-binding activity is a very powerful approach to promote cell adhesion, modulate cell behavior, and induce specific biological responses at the surface level. The aim of this Review is to illustrate the evolution of surface-coating molecules in this field: from peptides and proteins with relatively low integrin-binding activity and receptor selectivity to highly active and selective peptidomimetic ligands. In particular, we will bring into focus the difficult challenge of achieving selectivity between the two closely related integrin subtypes αvβ3 and α5β1. The functionalization of surfaces with such peptidomimetics opens the way for a new generation of highly specific cell-instructive surfaces to dissect the biological role of integrin subtypes and for application in tissue engineering and regenerative medicine.

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“…[9] Among the successful approaches, we would like to mention the g-amino acid RGD peptidomimetics containing a g-aminocyclopentane carboxylic acid or a 4aminoproline residue (14-membered ring), [10] the azabicyclic lactam RGD peptidomimetics (15-membered ring, with the scaffold mimicking a constrained dipeptide, e.g., ST1646), [11] and the b-amino acid RGD peptidomimetics, embodying b 3homoamino acids [12] (13-membered ring) or a cis-b-aminocyclopropane carboxylic acid (16-membered ring). [13] Up to now, a large number of linear or cyclic peptidic and peptidomimetic ligands have been developed, which are all related to the common recognition motif RGD [14] and a few potent ligands are presently in different stages of clinical trials for cancer therapy. Notwithstanding these recent achievements, the discovery of new ligands displaying high activity and selectivity together with an optimal pharmacological profile still remains a challenge.…”

Section: Introductionmentioning

confidence: 99%

Cyclic RGD Peptidomimetics Containing Bifunctional Diketopiperazine Scaffolds as New Potent Integrin Ligands

Marchini

Mingozzi

Colombo

et al. 2012

Chemistry A European J

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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 α(v)β(3) and α(v)β(5), which are involved in tumor angiogenesis. Nanomolar IC(50) values were obtained for the RGD peptidomimetics derived from trans DKP scaffolds (DKP-2-DKP-8). Conformational studies of the cyclic RGD peptidomimetics by (1)H 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 [Cβ(Arg)-Cβ(Asp) average distance ≥8.8 Å]. 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 α(v)β(3) complexed with the cyclic pentapeptide, Cilengitide. The highest affinity ligands produced top-ranked poses conserving all the important interactions of the X-ray complex.

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Die gerüststarre Aminosäure β‐Acc verleiht Integrinliganden Aktivität und Selektivität

Cited by 20 publications

References 24 publications

Konformative Kontrolle über Integrin‐Subtyp‐Selektivitäten in isoDGR‐Peptidmotiven: ein biologischer Schalter

Konformative Kontrolle über Integrin‐Subtyp‐Selektivitäten in isoDGR‐Peptidmotiven: ein biologischer Schalter

αvβ3‐ or α5β1‐Integrin‐Selective Peptidomimetics for Surface Coating

Cyclic RGD Peptidomimetics Containing Bifunctional Diketopiperazine Scaffolds as New Potent Integrin Ligands

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