Coibamide A Targets Sec61 to Prevent Biogenesis of Secretory and Membrane Proteins
Open Access
- 1 July 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Chemical Biology
- Vol. 15 (8), 2125-2136
- https://doi.org/10.1021/acschembio.0c00325
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 non-identical 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.Keywords
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Funding Information
- Sigrid Jus?liuksen S??ti?
- Takeda Science Foundation
- Fogarty International Center (TW006634-06)
- Japan Agency for Medical Research and Development (JP17am0101092j0001, JP18lm0203006j0002)
- Japan Society for the Promotion of Science (24659004)
- Academy of Finland (289737, 299762, 314672)
- National Institute of General Medical Sciences (R01GM132649)
- American Brain Tumor Association
This publication has 44 references indexed in Scilit:
- Published by American Chemical Society (ACS) ,2018
- Natural Products as Sources of New Drugs from 1981 to 2014Journal of Natural Products, 2016
- Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenograftsInvestigational New Drugs, 2015
- Efficient Synthesis and Stereochemical Revision of Coibamide AJournal of the American Chemical Society, 2015
- Solid-Phase Total Synthesis of the Proposed Structure of Coibamide A and Its Derivative: Highly Methylated Cyclic DepsipeptidesEuropean Journal of Organic Chemistry, 2015
- Synthesis and biological evaluation of the [d-MeAla11]-epimer of coibamide ABioorganic & Medicinal Chemistry Letters, 2015
- Five chemically rich species of tropical marine cyanobacteria of the genus Okeania gen. nov. (Oscillatoriales, Cyanoprokaryota)Journal of Phycology, 2013
- Coibamide A Induces mTOR-Independent Autophagy and Cell Death in Human Glioblastoma CellsPLOS ONE, 2013
- Natural Products as Chemical ProbesACS Chemical Biology, 2010
- Coibamide A, a Potent Antiproliferative Cyclic Depsipeptide from the Panamanian Marine Cyanobacterium Leptolyngbya sp.Journal of the American Chemical Society, 2008