Diastereomers of Coibamide A Show Altered Sec61 Client Selectivity and Ligand-Dependent Activity against Patient-Derived Glioma Stem-like Cells.
| Autor: | Mattos DR; Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States., Neves WD; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, United States., Kitamura T; Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan., Pradhan R; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, United States., Wan X; Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States., da Hora CC; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, United States., Tranter D; Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland., Kazemi S; Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States., Yu X; Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States., Tripathy N; Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States., Paavilainen VO; Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland., McPhail KL; Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States., Oishi S; Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.; Laboratory of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan., Badr CE; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, United States., Ishmael JE; Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2024 May 14; Vol. 7 (6), pp. 1823-1838. Date of Electronic Publication: 2024 May 14 (Print Publication: 2024). |
| DOI: | 10.1021/acsptsci.4c00049 |
| Abstrakt: | Coibamide A (CbA) is a cyanobacterial lariat depsipeptide that selectively inhibits multiple secreted and integral membrane proteins from entering the endoplasmic reticulum secretory pathway through binding the alpha subunit of the Sec61 translocon. As a complex peptide-based macrocycle with 13 stereogenic centers, CbA is presumed to adopt a conformationally restricted orientation in the ligand-bound state, resulting in potent antitumor and antiangiogenic bioactivity. A stereochemical structure-activity relationship for CbA was previously defined based on cytotoxicity against established cancer cell lines. However, the ability of synthetic isomers to inhibit the biosynthesis of specific Sec61 substrates was unknown. Here, we report that two less toxic diastereomers of CbA, [L-Hiv 2 ]-CbA and [L-Hiv 2 , L-MeAla 11 ]-CbA, are pharmacologically active Sec61 inhibitors. Both compounds inhibited the expression of a secreted reporter ( Gaussia luciferase), VEGF-A, and a Type 1 membrane protein (VCAM1), while [L-Hiv 2 ]-CbA also decreased the expression of ICAM1 and BiP/GRP78. Analysis of 43 different chemokines in the secretome of SF-268 glioblastoma cells revealed different inhibitory profiles for the two diastereomers. When the cytotoxic potential of CbA compounds was compared against a panel of patient-derived glioblastoma stem-like cells (GSCs), Sec61 inhibitors were remarkably toxic to five of the six GSCs tested. Each ligand showed a distinct cytotoxic potency and selectivity pattern for CbA-sensitive GSCs, with IC Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.) |
| Databáze: | MEDLINE |
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