Inhibiting AMPylation: a novel screen to identify the first small molecule inhibitors of protein AMPylation
Authors
Lewallen, Daniel M.Sreelatha, Anju
Dharmarajan, Venkatasubramanian
Madoux, Franck
Chase, Peter
Griffin, Patrick R.
Orth, Kim
Hodder, Peter
Thompson, Paul R
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2014-02-21Keywords
Adenosine MonophosphateAdenosine Triphosphate
Anti-Bacterial Agents
Bacterial Proteins
Drug Discovery
High-Throughput Screening Assays
Humans
Small Molecule Libraries
Vibrio Infections
Vibrio parahaemolyticus
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Therapeutics
Metadata
Show full item recordAbstract
Enzymatic transfer of the AMP portion of ATP to substrate proteins has recently been described as an essential mechanism of bacterial infection for several pathogens. The first AMPylator to be discovered, VopS from Vibrio parahemolyticus, catalyzes the transfer of AMP onto the host GTPases Cdc42 and Rac1. Modification of these proteins disrupts downstream signaling events, contributing to cell rounding and apoptosis, and recent studies have suggested that blocking AMPylation may be an effective route to stop infection. To date, however, no small molecule inhibitors have been discovered for any of the AMPylators. Therefore, we developed a fluorescence-polarization-based high-throughput screening assay and used it to discover the first inhibitors of protein AMPylation. Herein we report the discovery of the first small molecule VopS inhibitors (e.g., calmidazolium, GW7647, and MK886) with Ki's ranging from 6 to 50 muM and upward of 30-fold selectivity versus HYPE, the only known human AMPylator.Source
ACS Chem Biol. 2014 Feb 21;9(2):433-42. doi: 10.1021/cb4006886. Epub 2013 Nov 25. Link to article on publisher's siteDOI
10.1021/cb4006886Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50007Notes
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1021/cb4006886