Abstract：
: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 μM and upward of 30-fold selectivity versus HYPE, the only known human AMPylator.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Lewallen DM,Sreelatha A,Dharmarajan V,Madoux F,Chase P,Griffin PR,Orth K,Hodder P,Thompson PRdoi
10.1021/cb4006886subject
Has Abstractpub_date
2014-02-21 00:00:00pages
433-42issue
2eissn
1554-8929issn
1554-8937journal_volume
9pub_type
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