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

Abstract

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.

• Authors: Philipp Krastel, Silvio Roggo, Markus Schirle, Nathan T Ross, Francesca Perruccio, Peter Aspesi Jr, Thomas Aust, Kathrin Buntin, David Estoppey, Brigitta Liechty, Felipa Mapa, Klaus Memmert, Howard Miller, Xuewen Pan, Ralph Riedl, Christian Thibaut, Jason Thomas, Trixie Wagner, Eric Weber, Xiaobing Xie, Esther K Schmitt, Dominic Hoepfner
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 54 Issue 35 Pg. 10149-54 (Aug 24 2015) ISSN: 1521-3773 [Electronic] Germany
• PMID: 26179970 (Publication Type: Journal Article)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antifungal Agents
• Antineoplastic Agents
• EEF1A1 protein, human
• EEF1A2 protein, human
• Macrocyclic Compounds
• Peptide Elongation Factor 1
• nannocystin A

Topics

• Antifungal Agents (chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Candida albicans (drug effects)
• Cell Proliferation (drug effects)
• Genomics (methods)
• Humans
• Macrocyclic Compounds (chemistry, pharmacology)
• Molecular Structure
• Myxococcales (physiology)
• Neoplasms (drug therapy, pathology)
• Peptide Elongation Factor 1 (antagonists & inhibitors, genetics, metabolism)
• Proteomics (methods)
• Structure-Activity Relationship
• Tumor Cells, Cultured