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

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


Structural characterization of recombinant bovine Go alpha by spectroscopy and homology modeling
MEGA TİBER, PINAR; Orun, Oya; Nacar, Cevdet; Sezerman, Ugur Osman; Severcan, Feride; Severcan, Mete; Matagne, Andre; KAN, BEKİ (2011-01-01)
Go, a member of heterotrimeric guanine nucleotide-binding proteins, is the most abundant form of G protein in the central and peripheral nervous systems. Go alpha has a significant role in neuronal development and function but its signal transduction mechanism remains to be clarified.
Synthesis of peptide inhibitors for matrix metalloproteinase-2 and angiotensin converting enzyme /
Çiftçi, Burçe; Özçubukçu, Salih; Özen, Can; Department of Biotechnology (2014)
Matrix Metalloproteinases (MMPs) are one of the enzyme families of proteases that have zinc atom in the active site and they are involved in the degradation and regeneration of extracellular matrix. Specifically, they play an important role in tumor formation, tissue invasion, angiogenesis, and tumor metastasis. Matrix metalloprotease-2 (MMP-2) is a member of gelatinase class of MMP family and it has high activity in progression of skin, prostate, bladder, breast, lung, and ovary cancer. To control this inc...
Enhanced immunostimulatory activity of cyclic dinucleotides on mouse cells when complexed with a cell-penetrating peptide or combined with CpG
Yildiz, Soner; Alpdundar, Esin; Gungor, Bilgi; Kahraman, Tamer; Bayyurt, Banu; GÜRSEL, İHSAN; Gürsel, Mayda (2015-04-01)
Recognition of pathogen-derived nucleic acids by immune cells is critical for the activation of protective innate immune responses. Bacterial cyclic dinucleotides (CDNs) are small nucleic acids that are directly recognized by the cytosolic DNA sensor STING (stimulator of IFN genes), initiating a response characterized by proinflammatory cytokine and type I IFN production. Strategies to improve the immune stimulatory activities of CDNs can further their potential for clinical development. Here, we demonstrat...
Protein-Protein Interactions in Live Cells: Reinventing the Wheel
Son, Çağdaş Devrim (2018-12-13)
G protein-coupled receptors (GPCRs) are membrane proteins that mediate physiologicalresponse to a diverse array of stimuli. In humans, they mediate the action of hundreds ofpeptide hormones, sensory stimuli, odorants, neurotransmitters, and chemokines. GPCRs alsoare targets for ~40% of all currently marketed pharmaceuticals. These receptors traditionallybeen thought to act as monomeric units. However, recent evidence suggests that GPCRs mayform dimers as part of their normal trafficking and function. While ...
DynaDom: structure-based prediction of T cell receptor inter-domain and T cell receptor-peptide-MHC (class I) association angles
Hoffmann, Thomas; Marıon, Antoıne; Antes, Iris (Springer Science and Business Media LLC, 2017-02-02)
Background: T cell receptor (TCR) molecules are involved in the adaptive immune response as they distinguish between self- and foreign-peptides, presented in major histocompatibility complex molecules (pMHC). Former studies showed that the association angles of the TCR variable domains (Va/V beta) can differ significantly and change upon binding to the pMHC complex. These changes can be described as a rotation of the domains around a general Center of Rotation, characterized by the interaction of two highly...
Citation Formats
M. P. Khalily, S. GEREKÇİ, E. A. Gulec, C. Özen, and S. Özçubukçu, “Structure-based design, synthesis and anticancer effect of cyclic Smac-polyarginine peptides,” AMINO ACIDS, pp. 1607–1616, 2018, Accessed: 00, 2020. [Online]. Available: