Structure-based design, synthesis and anticancer effect of cyclic Smac-polyarginine peptides

Date

2018-11-01

Author

Khalily, Melek Parlak
GEREKÇİ, Selin
Gulec, Ezgi A.
Özen, Can
Özçubukçu, Salih

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

The second mitochondria-derived activator of caspase (Smac/DIABLO) is a pro-apoptotic protein that released from mitochondria into the cytosol when cells undergo apoptosis. Smac promotes caspase activation by binding the inhibitors of apoptosis proteins (IAP), particularly XIAP and eliminating their inhibitory activity. Although the seven N-terminal amino acids AVPIAQK (SmacN7) of Smac protein is able to elicit an anticancer response by itself, it is neither cell-permeable nor stable in the cellular environment. Thus, the use of SmacN7 derivatives and mimetics is an alluring field for cancer therapy. In this study, heptamer Smac peptide was fused to a well-known octaarginine cell-penetrating peptide for promoting its intracellular access. Both therapeutic Smac part and cell-penetrating octaarginine parts of the peptide sequence constrained in a cyclic structure so as to enhance the apoptosis-inducing potential of the SmacN7 peptide. Biological assays interestingly showed that cyclic peptides P4, P5 and P7 gave rise to a significant level of cytotoxicity and apoptosis mediated cell death in multiple myeloma tumor cells (MM) comparing to linear peptide.

Subject Keywords

Smac, DIABLO, Constrained peptides, IAP, Proapoptotic peptides, CPPs, Multiple myeloma

URI

https://hdl.handle.net/11511/31105

Collections

Graduate School of Natural and Applied Sciences, Article