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Diastereomers of Coibamide A Show Altered Sec61 Client Selectivity and Ligand-Dependent Activity against
Daphne R Mattos1, Willian das Neves2, Takashi Kitamura3
1Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon 97331, United States.
Abstract:
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-Hiv2]-CbA and [L-Hiv2, L-MeAla11]-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-Hiv2]-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 IC50 values ranging from subnanomolar to low micromolar concentrations. Together, these findings highlight the extreme sensitivity of GSCs to Sec61 modulation and the importance of ligand stereochemistry in determining the spectrum of inhibited Sec61 client proteins.
Insights
Two Coibamide A (CbA) isomers, [L-Hiv2]-CbA and [L-Hiv2, L-MeAla11]-CbA, effectively inhibit Sec61 translocon activity. These compounds show potent toxicity against glioblastoma stem-like cells (GSCs), highlighting Sec61 modulation
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Coibamide A (CbA) is a cyanobacterial depsipeptide that targets the Sec61 translocon, inhibiting protein transport into the endoplasmic reticulum.
- CbA exhibits antitumor and antiangiogenic properties, with a previously established structure-activity relationship based on cytotoxicity.
- The impact of synthetic CbA isomers on Sec61 substrate biosynthesis remained largely unexplored.
Purpose of the Study:
- To investigate the Sec61 inhibitory activity of two less toxic Coibamide A diastereomers: [L-Hiv2]-CbA and [L-Hiv2, L-MeAla11]-CbA.
- To determine the effects of these isomers on the expression of specific Sec61 substrates, including secreted, membrane-bound proteins, and chemokines.
- To evaluate the cytotoxic potential of CbA isomers against patient-derived glioblastoma stem-like cells (GSCs).
Main Methods:
- Synthesis and characterization of CbA diastereomers.
- Assay of Sec61 inhibitory activity by measuring the expression of reporter proteins (Gaussia luciferase), VEGF-A, VCAM1, ICAM1, and BiP/GRP78.
- Secretome analysis of 43 chemokines in SF-268 glioblastoma cells.
- Cytotoxicity assays against a panel of patient-derived glioblastoma stem-like cells (GSCs).
Main Results:
- Both [L-Hiv2]-CbA and [L-Hiv2, L-MeAla11]-CbA demonstrated pharmacological activity as Sec61 inhibitors.
- [L-Hiv2]-CbA inhibited ICAM1 and BiP/GRP78 expression in addition to secreted reporter, VEGF-A, and VCAM1.
- The two diastereomers exhibited distinct inhibitory profiles for various chemokines in glioblastoma cells.
- CbA compounds were highly toxic to five out of six tested GSCs, with varying potency (subnanomolar to low micromolar IC50 values).
Conclusions:
- The study confirms that specific Coibamide A diastereomers are potent Sec61 inhibitors.
- Ligand stereochemistry critically influences the spectrum of inhibited Sec61 client proteins.
- Glioblastoma stem-like cells exhibit extreme sensitivity to Sec61 pathway modulation by CbA analogs, suggesting therapeutic potential.
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