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AVPI-(Ala-Val-Pro-Ile) and RGD-(Arg-Gly-Asp) peptides have recently attracted a growing interest in the anticancer drug design and development. Following the concept of combining two fragments with different functionalities in order to achieve increased effects, we present herein the synthesis of two AVPI-RGD peptides. The impact of the performed chemical modifications on the anti-proliferative activity of these peptides was evaluated at MDA-MB-231 cancer cells. It was found that the conjugated peptide with modifications at proline and arginine residues showed a higher anti-proliferative effect than the parent AVPI-RGD molecule. Furthermore, it was observed that the effect of AVHypI-AgbGD vs. that of its co-administrated structural subunits was higher. The results obtained in this work suggested that the introduced substitutions and the conjugation of the two functional motifs benefit the anti-proliferative activity of the parent peptides. [ABSTRACT FROM AUTHOR]

Peptides have been developed during the last decade as an alternative for delivery and targeting of drugs, and for the visualization of tumors. In contrast to the antibodies, the peptides are smaller and can be delivered to the cytoplasm by various mechanisms. RGD peptides have been developed as potent integrin ligands and antagonists that inhibit the adhesion and formation of tumor metastases or directly induce apoptosis by activating caspases. A series of short RGD mimetics and their conjugates are synthesized and their cytotoxic activity against four cancer cell lines is examined. RGD peptides modified by shorter homologues of with arginine (α-amino-4-guanidinobutyric acid (Agb) and α-amino-3-guanidino-propionic acid (Agp)) show an increase of the cytotoxic effect compared to that of the parent RGD peptide. [ABSTRACT FROM AUTHOR]

To elucidate the structural features determining δ-opioid receptor properties of enkephalin analogues containing Cys(O2NH2) in position 2, a series of Cys2-containing derivatives were synthesized and tested for their effectiveness in depressing electrically evoked contractions of the mouse vas deferens (predominantly enkephalin-selective δ-opioid receptors) and the guinea-pig ileum (μ- and κ-opioid receptors). The peptidase resistance of the compounds was also tested. The ratio IC50 in the guinea-pig ileum/IC50 in the mouse vas deferens, indicating selectivity for δ-opioid receptors, was high for Cys(O2NH2)2-containing analogues and especially for [Cys(O2NH2)2, Leu5]enkephalin, which was about seven times more selective than δ-opioid receptor selective ligand cyclic [d-Pen2, d-Pen5]enkephalin (DPDPE). The dissociation constant (KA) and relative efficacy (erel) of the compounds in the mouse-isolated vas deferens were determined using explicit formulae derived by fitting of the data points with two-parametric hyperbolic function. The obtained values for KA and erel suggest that: (i) incorporation of Cys(O2NH2)2 in the molecule of [Leu5]enkephalin highly increases the efficacy and does not change significantly the affinity of the respective analogues to δ-opioid receptors; [Cys(O2NH2)2, Leu5]enkephalin has higher affinity than DPDPE, but is less resistant to enzyme degradation; the effect of this modification on the efficacy is decreased when methionine is in position 5; (ii) d-configuration of Cys(O2NH2)2-containing analogues increases their peptidase resistance, but reduces efficacy and affinity of the peptides towards δ-opioid receptors; (iii) the substitution of Cys(O2NH2) with Hcy(O2NH2) reduces the efficacy, affinity and potency of the respective analogues and maintains their sensitivity to endogenous peptidases; (iv) the substitution of the sulfonamide group with benzyl group in the molecule of Cys in position 2 decreases their efficacy and affinity toward δ-opioid receptors, but attaches resistance to enzyme degradation. The results obtained in this study allow: (i) to involve the receptor affinity and agonist efficacy as drug-design consideration for δ-opioid receptor properties of newly synthesized compounds and (ii) to characterize some of the structural features, which set the pattern for their opioid profiles. [Copyright &y& Elsevier]