ArticleACS chemical biology2020
Coibamide A Targets Sec61 to Prevent Biogenesis of Secretory and Membrane Proteins.
Article in ACS chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 65 citations in OpenAlex.
- Cotranslational membrane protein biogenesis by an EMC-bound translocon.Nature structural & molecular biology · 2026Article
- A mycobacterial Sec61 inhibitor disrupts lysosome function by blocking Vacuolar-ATPase biosynthesis.European journal of cell biology · 2026Article
- Identification of Hoiamide A as an Inducer of Oxidative and Endoplasmic Reticulum Secretory Pathway Stress.Journal of natural products · 2026Article
- Green genes from blue greens: challenges and solutions to unlocking the potential of cyanobacteria in drug discovery.Natural product reports · 2026Review
- A light-resuming strategy as a screening method for selecting Sec61 inhibitors down-modulating PD-L1 expression.Nature communications · 2025Article
- Cyanobacterial Peptides in Anticancer Therapy: A Comprehensive Review of Mechanisms, Clinical Advances, and Biotechnological Innovation.Marine drugs · 2025Review
- Structural Modifications Reveal Dual Functions of the C-4 Carbonyl Group in the Fatty Acid Chain of Ipomoeassin F.Molecules (Basel, Switzerland) · 2025Article
- Exploring the ER channel protein Sec61: recent advances in pathophysiological significance and novel pharmacological inhibitors.Frontiers in pharmacology · 2025Review
- The prolyl isomerase FKBP11 is a secretory translocon accessory factor.Molecular biology of the cell · 2024Article
- Review
- A unifying model for membrane protein biogenesis.Nature structural & molecular biology · 2024Review
- Article
- Diastereomers of Coibamide A Show Altered Sec61 Client Selectivity and Ligand-Dependent Activity against Patient-Derived Glioma Stem-like Cells.ACS pharmacology & translational science · 2024Article
- Design of Synthetic Surrogates for the Macrolactone Linker Motif in Coibamide A.ACS medicinal chemistry letters · 2023Article
- Signal peptide mimicry primes Sec61 for client-selective inhibition.Nature chemical biology · 2023Article
- A common mechanism of Sec61 translocon inhibition by small molecules.Nature chemical biology · 2023Article
- Achieving the promise and avoiding the peril of chemical probes using genetics.Current opinion in structural biology · 2023Review
- The Biogenesis of Multipass Membrane Proteins.Cold Spring Harbor perspectives in biology · 2023Review
- Mechanism of signal-anchor triage during early steps of membrane protein insertion.Molecular cell · 2023Article
- Structural insights into TRAP association with ribosome-Sec61 complex and translocon inhibition by a CADA derivative.Science advances · 2023Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
Abstract
Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against human cancer cells and a unique selectivity profile. Despite promising antitumor activity, the mechanism of cytotoxicity and specific cellular target of CbA remain unknown. Here, we develop an optimized synthetic CbA photoaffinity probe (photo-CbA) and use it to demonstrate that CbA directly targets the Sec61α subunit of the Sec61 protein translocon. CbA binding to Sec61 results in broad substrate-nonselective inhibition of ER protein import and potent cytotoxicity against specific cancer cell lines. CbA targets a lumenal cavity of Sec61 that is partially shared with known Sec61 inhibitors, yet profiling against resistance conferring Sec61α mutations identified from human HCT116 cells suggests a distinct binding mode for CbA. Specifically, despite conferring strong resistance to all previously known Sec61 inhibitors, the Sec61α mutant R66I remains sensitive to CbA. A further unbiased screen for Sec61α resistance mutations identified the CbA-resistant mutation S71P, which confirms nonidentical binding sites for CbA and apratoxin A and supports the susceptibility of the Sec61 plug region for channel inhibition. Remarkably, CbA, apratoxin A, and ipomoeassin F do not display comparable patterns of potency and selectivity in the NCI60 panel of human cancer cell lines. Our work connecting CbA activity with selective prevention of secretory and membrane protein biogenesis by inhibition of Sec61 opens up possibilities for developing new Sec61 inhibitors with improved drug-like properties that are based on the coibamide pharmacophore.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.