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Mar. Drugs 2018, 16(10), 395; https://doi.org/10.3390/md16100395

A High-Content Screening Assay for the Discovery of Novel Proteasome Inhibitors from Formosan Soft Corals

1
Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80441, Taiwan
2
Department of Microbiology and Immunology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
*
Authors to whom correspondence should be addressed.
Received: 9 October 2018 / Revised: 17 October 2018 / Accepted: 18 October 2018 / Published: 21 October 2018
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Abstract

The ubiquitin-proteasome system (UPS) is a major proteolytic pathway that safeguards protein homeostasis. The main 26S proteasome consists of a 20S catalytic core proteasome and a 19S substrate recognition proteasome. UPS dysfunction underlies many important clinical diseases involving inflammation, tumors, and neurodegeneration. Currently, three 20S proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, have been approved for the treatment of multiple myeloma. We aim to screen UPS inhibitors for biomedical purposes. The protein interaction network of human cytomegalovirus UL76 targets UPS, resulting in aggregations of ubiquitinated proteins termed aggresomes. In this study, we demonstrated that cell-based high-content measurements of EGFP-UL76 aggresomes responded to bortezomib and MG132 treatment in a dose-dependent manner. Employing this high-content screening (HCS) assay, we screened natural compounds purified from Formosan soft corals. Four cembrane-based compounds, sarcophytonin A (1), sarcophytoxide (2), sarcophine (3), and laevigatol A (4), were found to enhance the high-content profiles of EGFP-UL76 aggresomes with relative ratios of 0.2. By comparison to the mechanistic action of proteasome inhibitors, compounds 1 and 3 modulated the accumulation of ubiquitinated proteins, with a unique pattern likely targeting 19S proteasome. We confirmed that the EGFP-UL76 aggresome-based HCS system greatly improves the efficacy and sensitivity of the identification of proteasome inhibitors. View Full-Text
Keywords: proteasome inhibitor; soft coral; high-content screening; cembrane proteasome inhibitor; soft coral; high-content screening; cembrane
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Ling, X.-H.; Wang, S.-K.; Huang, Y.-H.; Huang, M.-J.; Duh, C.-Y. A High-Content Screening Assay for the Discovery of Novel Proteasome Inhibitors from Formosan Soft Corals. Mar. Drugs 2018, 16, 395.

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