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.

Brindisi, M., Maramai, S., Brogi, S., Fanigliulo, E., Butini, S., Guarino, E., et al. (2016). Development of novel cyclic peptides as pro-apoptotic agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 117, 301-320 [10.1016/j.ejmech.2016.04.001].

Development of novel cyclic peptides as pro-apoptotic agents

BRINDISI, MARGHERITA;MARAMAI, SAMUELE;FANIGLIULO, EMANUELA;BUTINI, STEFANIA;GUARINO, EGERIA;CASAGNI, ALICE;LAMPONI, STEFANIA;BONECHI, CLAUDIA;FINETTI, FEDERICA;VALENTI, SALVATORE;MORBIDELLI, LUCIA;DONATI, ALESSANDRO;BALDARI, COSIMA;CAMPIANI, GIUSEPPE;ULIVIERI, CRISTINA;GEMMA, SANDRA
2016-01-01

Abstract

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.
Brindisi, M., Maramai, S., Brogi, S., Fanigliulo, E., Butini, S., Guarino, E., et al. (2016). Development of novel cyclic peptides as pro-apoptotic agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 117, 301-320 [10.1016/j.ejmech.2016.04.001].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/995494