Dataset Information

Design of Peptoid-peptide Macrocycles to Inhibit the ?-catenin TCF Interaction in Prostate Cancer.

ABSTRACT: New chemical inhibitors of protein-protein interactions are needed to propel advances in molecular pharmacology. Peptoids are peptidomimetic oligomers with the capability to inhibit protein-protein interactions by mimicking protein secondary structure motifs. Here we report the in silico design of a macrocycle primarily composed of peptoid subunits that targets the ?-catenin:TCF interaction. The ?-catenin:TCF interaction plays a critical role in the Wnt signaling pathway which is over-activated in multiple cancers, including prostate cancer. Using the Rosetta suite of protein design algorithms, we evaluate how different macrocycle structures can bind a pocket on ?-catenin that associates with TCF. The in silico designed macrocycles are screened in vitro using luciferase reporters to identify promising compounds. The most active macrocycle inhibits both Wnt and AR-signaling in prostate cancer cell lines, and markedly diminishes their proliferation. In vivo potential is demonstrated through a zebrafish model, in which Wnt signaling is potently inhibited.

SUBMITTER: Schneider JA

PROVIDER: S-EPMC6199279 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer.

Schneider Jeffrey A JA Craven Timothy W TW Kasper Amanda C AC Yun Chi C Haugbro Michael M Briggs Erica M EM Svetlov Vladimir V Nudler Evgeny E Knaut Holger H Bonneau Richard R Garabedian Michael J MJ Kirshenbaum Kent K Logan Susan K SK

Nature communications 20181023 1

New chemical inhibitors of protein-protein interactions are needed to propel advances in molecular pharmacology. Peptoids are peptidomimetic oligomers with the capability to inhibit protein-protein interactions by mimicking protein secondary structure motifs. Here we report the in silico design of a macrocycle primarily composed of peptoid subunits that targets the β-catenin:TCF interaction. The β-catenin:TCF interaction plays a critical role in the Wnt signaling pathway which is over-activated ...[more]

PMID: 30352998

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Project description:Osteosarcoma, a highly metastasizing bone neoplasm, is a leading cause of death and disability in children and adolescents worldwide. Osteosarcoma is only suboptimally responsive to surgery and radio- and chemotherapy, that too with adverse side effects. Hence, there is a necessary need for safer alternative therapeutic approaches. This study evaluated the anticancer effects of the semi-synthetic compound, pterostilbene-isothiocyanate (PTER-ITC), on human osteosarcoma MG-63 cells through cytotoxicity, wound-healing, and transwell-migration assays. Results showed that PTER-ITC specifically inhibited the survival, proliferation, and migration of osteosarcoma cells. PTER-ITC induced apoptosis in MG-63 cells by disrupting mitochondrial membrane potential, as evident from the outcomes of different cytological staining. The antimetastatic potential of PTER-ITC was evaluated through immunostaining, RT-qPCR, and immunoblotting. In silico (molecular docking and dynamic simulation) and, subsequently, biochemical [co-immunoprecipitation (Co-IP) and luciferase reporter] assays deciphered the underlying mode-of-action of this compound. PTER-ITC increased E-cadherin and reduced N-cadherin levels, thereby facilitating the reversal of epithelial-mesenchymal transition (EMT). It also modulated the expressions of proliferative cell nuclear antigen (PCNA), caspase-3, poly [ADP-ribose] polymerase (PARP-1) and matrix metalloproteinase-2/9 (MMPs-2/9) at transcriptional and translational levels. PTER-ITC interfered with the β-catenin/transcription factor-4 (TCF-4) interaction in silico by occupying the β-catenin binding site on TCF-4, confirmed by their reduced physical interactions (Co-IP assay). This inhibited transcriptional activation of TCF-4 by β-catenin (as shown by luciferase reporter assay). In conclusion, PTER-ITC exhibited potent anticancer effects in vitro against human osteosarcoma cells by abrogating the β-catenin/TCF-4 interaction. Altogether, this study suggests that PTER-ITC may be regarded as a new approach for osteosarcoma treatment.

Dataset Information

Design of Peptoid-peptide Macrocycles to Inhibit the ?-catenin TCF Interaction in Prostate Cancer.

Publications

Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer.

Similar Datasets

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