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Title: Development of novel cyclic peptides as pro-apoptotic agents
Authors: Brindisi, Margherita 
Maramai, Samuele 
Brogi, Simone
Fanigliulo, Emanuela
Butini, Stefania 
Guarino, Egeria
Casagni, Alice
Lamponi, Stefania 
Bonechi, Claudia 
Nathwani, Seema M
Finetti, Federica 
Ragonese, Francesco
Arcidiacono, Paola
Campiglia, Pietro
Valenti, Salvatore
Novellino, Ettore
Spaccapelo, Roberta
Morbidelli, Lucia
Zisterer, Daniela M
Williams, Clive D
Donati, Alessandro 
Baldari, Cosima
Campiani, Giuseppe 
Ulivieri, Cristina
Gemma, Sandra 
Keywords: Anticancer agents; Bcl-2; Confocal microscopy; Cyclic peptides; FACS analysis; Molecular modeling; NMR studies; Nur77; Peptidomimetics; Pro-apoptotic agents; Tubulin
Issue Date: 2016
Project: None 
Our recent finding that paclitaxel behaves as a peptidomimetic of the endogenous protein Nur77 inspired the design of two peptides (PEP1 and PEP2) reproducing the effects of paclitaxel on Bcl-2 and tubulin, proving the peptidomimetic nature of paclitaxel. Starting from these peptide-hits, we herein describe the synthesis and the biological investigation of linear and cyclic peptides structurally related to PEP2. While linear peptides (2a,b, 3a,b, 4, 6a-f) were found inactive in cell-based assays, biological analysis revealed a pro-apoptotic effect for most of the cyclic peptides (5a-g). Cellular permeability of 5a (and also of 2a,b) on HL60 cells was assessed through confocal microscopy analysis. Further cellular studies on a panel of leukemic cell lines (HL60, Jurkat, MEC, EBVB) and solid tumor cell lines (breast cancer MCF-7 cells, human melanoma A375 and 501Mel cells, and murine melanoma B16F1 cells) confirmed the pro-apoptotic effect of the cyclic peptides. Cell cycle analysis revealed that treatment with 5a, 5c, 5d or 5f resulted in an increase in the number of cells in the sub-G0/G1 peak. Direct interaction with tubulin (turbidimetric assay) and with microtubules (immunostaining experiments) was assessed in vitro for the most promising compounds.
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2016.04.001
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