Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties

Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. I...

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Published in:Angewandte Chemie (International ed.) 2015-08, Vol.54 (35), p.10149-10154
Main Authors: Krastel, Philipp, Roggo, Silvio, Schirle, Markus, Ross, Nathan T., Perruccio, Francesca, Aspesi Jr, Peter, Aust, Thomas, Buntin, Kathrin, Estoppey, David, Liechty, Brigitta, Mapa, Felipa, Memmert, Klaus, Miller, Howard, Pan, Xuewen, Riedl, Ralph, Thibaut, Christian, Thomas, Jason, Wagner, Trixie, Weber, Eric, Xie, Xiaobing, Schmitt, Esther K., Hoepfner, Dominic
Format: Article
Language:English
Subjects:
Antifungal Agents - chemistry
Antifungal Agents - pharmacology
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Candida albicans - drug effects
Cell Proliferation - drug effects
didemnin B
elongation factor 1α
Genomics - methods
Humans
Macrocyclic Compounds - chemistry
Macrocyclic Compounds - pharmacology
Molecular Structure
myxobacteria
Myxococcales - physiology
nannocystin A
natural products
Neoplasms - drug therapy
Neoplasms - pathology
Peptide Elongation Factor 1 - antagonists & inhibitors
Peptide Elongation Factor 1 - genetics
Peptide Elongation Factor 1 - metabolism
Proteomics - methods
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a class of novel cyclic lactone inhibitors of elongation factor 1. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti‐fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF‐1α) as the primary target for this compound class. Nannocystin A (1) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site of 1 with the anti‐cancer compound didemnin B on EF‐1α. This myxobacterial chemotype thus offers an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1. The cyclic lactone nannocystin A was isolated from myxobacteria of the Nannocystis species. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1α (EF‐1α) as the primary target for this compound class.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201505069