A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2006-02-01Keywords
AcetamidesAmidines
Animals
Drug Design
Enzyme Activation
Enzyme Inhibitors
Hydrocarbons, Fluorinated
Hydrolases
Kinetics
Biochemistry
Enzymes and Coenzymes
Medicinal-Pharmaceutical Chemistry
Therapeutics
Metadata
Show full item recordAbstract
Protein arginine deiminase 4 (PAD4) is a calcium-dependent transcriptional corepressor that has been implicated in the onset and progression of rheumatoid arthritis. Herein we describe the synthesis and in vitro evaluation of a fluoroacetamidine-containing compound, N-alpha-benzoyl-N5-(2-fluoro-1-iminoethyl)-l-ornithine amide, 1, hereafter referred to as F-amidine, that is the most potent PAD4 inhibitor ever described. Additional studies described herein indicate that F-amidine can also inhibit PAD4 activity in vivo. The bioavailability of this compound suggests that F-amidine will be a powerful chemical probe of PAD4 function that can be used to dissect the roles of this enzyme in both rheumatoid arthritis and transcriptional control. The fact that inhibition is of an irreversible nature suggests that, with appropriate functionalization, F-amidine analogues will be robust activity-based protein-profiling and proteomic capture reagents.Source
J Am Chem Soc. 2006 Feb 1;128(4):1092-3. Link to article on publisher's siteDOI
10.1021/ja0576233Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50075Notes
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1021/ja0576233