Biosynthesis and Chemical Diversification of Verucopeptin Leads to Structural and Functional Versatility

Lei Zhang; Yuezhou Wang; Wei Huang; Yanling Wei; Zile Jiang; Lulin Kong; An-An Wu; Zhiyu Hu; Huiying Huang; Qingyan Xu; Li Li; Xianming Deng

doi:10.1021/acs.orglett.0c01387

Biosynthesis and Chemical Diversification of Verucopeptin Leads to Structural and Functional Versatility

Org Lett. 2020 Jun 5;22(11):4366-4371. doi: 10.1021/acs.orglett.0c01387. Epub 2020 May 27.

Authors

Lei Zhang¹, Yuezhou Wang¹, Wei Huang¹, Yanling Wei¹, Zile Jiang¹, Lulin Kong¹, An-An Wu², Zhiyu Hu¹, Huiying Huang¹, Qingyan Xu¹, Li Li¹, Xianming Deng¹

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
² State Key Laboratory for Physical Chemistry of Solid Surface, Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361105, China.

PMID: 32459492
DOI: 10.1021/acs.orglett.0c01387

Abstract

A synthesis program for structurally complex macrocycles is very challenging. Herein, we propose a biosynthesis pathway of the pyranylated cyclodepsipeptide verucopeptin to make enough supply and to diversify verucopeptin by genetic manipulation and one-step semisynthesis. The synthesis relies on the intrinsic reactivity of the interchangeable hemiketal pyrane and opened keto along with adjacent alkene. Biological evaluation of verucopeptin-oriented analogs delivers a potent AMP-activated protein kinase (AMPK) agonist, antibacterial agent, and selective NFκB modulator.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Actinomadura / chemistry
Anti-Bacterial Agents / biosynthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Depsipeptides / biosynthesis
Depsipeptides / chemistry
Depsipeptides / pharmacology*
HEK293 Cells
Humans
Microbial Sensitivity Tests
Molecular Structure
NF-kappa B / antagonists & inhibitors*
NF-kappa B / metabolism
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Signal Transduction / drug effects
Staphylococcus aureus / drug effects*

Substances

Anti-Bacterial Agents
Depsipeptides
NF-kappa B
Protein Kinase Inhibitors
verucopeptin
AMP-Activated Protein Kinases