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The Sam-Sam interaction between Ship2 and the EphA2 receptor: design and analysis of peptide inhibitors (52 visite)
Sci Rep (ISSN: 2045-2322electronic, 2045-2322linking), 2017 Dec 12; 7(1): 17474-17474.
Tipo di articolo: Journal Article,
Impact factor: 4.259
Impact factor a 5 anni: 4.847
Parole chiave: Non disponibili.
Url: Non disponibile.
The lipid phosphatase Ship2 represents a drug discovery target for the treatment of different diseases, including cancer. Its C-terminal sterile alpha motif domain (Ship2-Sam) associates with the Sam domain from the EphA2 receptor (EphA2-Sam). This interaction is expected to mainly induce pro-oncogenic effects in cells therefore, inhibition of the Ship2-Sam/EphA2-Sam complex may represent an innovative route to discover anti-cancer therapeutics. In the present work, we designed and analyzed several peptide sequences encompassing the interaction interface of EphA2-Sam for Ship2-Sam. Peptide conformational analyses and interaction assays with Ship2-Sam conducted through diverse techniques (CD, NMR, SPR and MST), identified a positively charged penta-amino acid native motif in EphA2-Sam, that once repeated three times in tandem, binds Ship2-Sam. NMR experiments show that the peptide targets the negatively charged binding site of Ship2-Sam for EphA2-Sam. Preliminary in vitro cell-based assays indicate that -at 50 microM concentration- it induces necrosis of PC-3 prostate cancer cells with more cytotoxic effect on cancer cells than on normal dermal fibroblasts. This work represents a pioneering study that opens further opportunities for the development of inhibitors of the Ship2-Sam/EphA2-Sam complex for therapeutic applications.
*** IBB - CNR ***
Institute of Biostructures and Bioimaging (IBB), CNR, via Mezzocannone 16, 80134, Naples, Italy., Department of Pharmacy, Research Centre on Bioactive Peptides (CIRPeB), University of Naples "Federico II", Via Mezzocannone 16, 80134, Naples, Italy., Institute of Biostructures and Bioimaging (IBB), CNR, via Mezzocannone 16, 80134, Naples, Italy. firstname.lastname@example.org.,
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