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PMID: 17964793 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Profiling Protein Arginine Deiminase 4 (PAD4): a novel screen to identify PAD4 inhibitors.

Bioorganic & medicinal chemistry ·Vol. 16 ·No. 2 ·2008-01-15 ·Pages 739-45

Knuckley B, Luo Y, Thompson PR

Abstract

Protein Arginine Deiminase 4 (PAD4) has emerged as a leading target for the development of a Rheumatoid Arthritis (RA) pharmaceutical. Herein, we describe the development of a novel screen for PAD4 inhibitors that is based on a PAD4-targeted Activity-Based Protein Profiling reagent, denoted Rhodamine-conjugated F-Amidine (RFA). This screen was validated by screening 10 Disease Modifying Anti-Rheumatic Drugs (DMARDs) and identified streptomycin, minocycline, and chlortetracycline as micromolar inhibitors of PAD4 activity.

MeSH Terms
Arthritis, Rheumatoid/drug therapy,enzymology Chlortetracycline/pharmacology Combinatorial Chemistry Techniques Enzyme Inhibitors/chemical synthesis,pharmacology Fluorescent Dyes/chemical synthesis,pharmacology Hydrolases/antagonists & inhibitors Minocycline/pharmacology Models, Biological Molecular Structure Protein-Arginine Deiminase Type 4 Protein-Arginine Deiminases Streptomycin/pharmacology Tetracycline/pharmacology
Chemicals
Enzyme Inhibitors Fluorescent Dyes Hydrolases Protein-Arginine Deiminase Type 4 Protein-Arginine Deiminases Tetracycline Minocycline Chlortetracycline Streptomycin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Knuckley Bryan
Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, SC 29208, USA.
Luo Yuan
Thompson Paul R
References (31)
31 references, click to expand
  1. Newer approaches to the treatment of rheumatoid arthritis.
    WMJ. 2003;102(7):34-7 PMID: 14711022
  2. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide.
    Arthritis Rheum. 2000 Jan;43(1):155-63 PMID: 10643712
  3. Kinetic characterization of protein arginine deiminase 4: a transcriptional corepressor implicated in the onset and progression of rheumatoid arthritis.
    Biochemistry. 2005 Aug 9;44(31):10570-82 PMID: 16060666
  4. Protein arginine deiminase 4: evidence for a reverse protonation mechanism.
    Biochemistry. 2007 Jun 5;46(22):6578-87 PMID: 17497940
  5. Effect of tetracycline on the phagocytic function of human leukocytes.
    J Infect Dis. 1974 Oct;130(4):412-5 PMID: 4613762
  6. A non-antibacterial chemically-modified tetracycline inhibits mammalian collagenase activity.
    J Dent Res. 1987 Aug;66(8):1310-4 PMID: 3040832
  7. Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity.
    Arthritis Res Ther. 2005;7(3):R458-67 PMID: 15899032
  8. ABAP: antibody-based assay for peptidylarginine deiminase activity.
    Anal Biochem. 2007 Oct 15;369(2):232-40 PMID: 17716614
  9. A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases.
    J Am Chem Soc. 2007 Aug 8;129(31):9594-5 PMID: 17629278
  10. Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock?
    ACS Chem Biol. 2006 Aug 22;1(7):433-41 PMID: 17168521
  11. Antibiotic therapy for rheumatoid arthritis. Scientific and anecdotal appraisals.
    Rheum Dis Clin North Am. 1995 Aug;21(3):817-34 PMID: 8619101
  12. Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization.
    Biochemistry. 2006 Oct 3;45(39):11727-36 PMID: 17002273
  13. A fluoroacetamidine-based inactivator of protein arginine deiminase 4: design, synthesis, and in vitro and in vivo evaluation.
    J Am Chem Soc. 2006 Feb 1;128(4):1092-3 PMID: 16433522
  14. PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis.
    Rheumatol Int. 2007 Jul;27(9):827-33 PMID: 17265154
  15. Should tetracyclines be used in arthritis?
    J Rheumatol. 1992 Oct;19(10):1495-7 PMID: 1464857
  16. Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations.
    Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9685-90 PMID: 16769901
  17. ABC of rheumatology. Rheumatoid arthritis--I: Clinical features and diagnosis.
    BMJ. 1995 Mar 4;310(6979):587-90 PMID: 7888939
  18. A colorimetric 96-well microtiter plate assay for the determination of enzymatically formed citrulline.
    Anal Biochem. 2000 Nov 15;286(2):257-64 PMID: 11067748
  19. The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues.
    J Immunol. 1999 Jan 1;162(1):585-94 PMID: 9886436
  20. Discovering potent and selective reversible inhibitors of enzymes in complex proteomes.
    Nat Biotechnol. 2003 Jun;21(6):687-91 PMID: 12740587
  21. Association between PADI4 and rheumatoid arthritis: a meta-analysis.
    Rheumatology (Oxford). 2006 Jul;45(7):804-7 PMID: 16449362
  22. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis.
    Nat Genet. 2003 Aug;34(4):395-402 PMID: 12833157
  23. Activity-based protein profiling reagents for protein arginine deiminase 4 (PAD4): synthesis and in vitro evaluation of a fluorescently labeled probe.
    J Am Chem Soc. 2006 Nov 15;128(45):14468-9 PMID: 17090024
  24. Therapeutic strategies for rheumatoid arthritis.
    Nat Rev Drug Discov. 2003 Jun;2(6):473-88 PMID: 12776222
  25. Minocycline reduces gingival collagenolytic activity during diabetes. Preliminary observations and a proposed new mechanism of action.
    J Periodontal Res. 1983 Sep;18(5):516-26 PMID: 6315909
  26. Tetracyclines inhibit human synovial collagenase in vivo and in vitro.
    J Rheumatol. 1987 Feb;14(1):28-32 PMID: 3033237
  27. Discovery of an exceptionally potent and selective class of fatty acid amide hydrolase inhibitors enlisting proteome-wide selectivity screening: concurrent optimization of enzyme inhibitor potency and selectivity.
    Bioorg Med Chem Lett. 2005 Mar 1;15(5):1423-8 PMID: 15713400
  28. A continuous spectrophotometric assay method for peptidylarginine deiminase type 4 activity.
    Anal Biochem. 2005 Dec 15;347(2):176-81 PMID: 16266680
  29. Inhibition of trypsin-like cysteine proteinases (gingipains) from Porphyromonas gingivalis by tetracycline and its analogues.
    Antimicrob Agents Chemother. 2001 Oct;45(10):2871-6 PMID: 11557483
  30. Single-blind randomized trial of combination antibiotic therapy in rheumatoid arthritis.
    J Rheumatol. 2006 Feb;33(2):224-7 PMID: 16465651
  31. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies.
    J Clin Invest. 1998 Jan 1;101(1):273-81 PMID: 9421490
Article Info
Journal
Bioorganic & medicinal chemistry
Abbr.
Bioorg Med Chem
ISSN
1464-3391
DOI
10.1016/j.bmc.2007.10.021
Published
2008-01-15
Epub
2007-00-13
Pages
739-45
Language
English
Region
England
NLM ID
9413298
PMCID
PMC2267747
Subset
IM
Grants
NIGMS NIH HHS · R01 GM079357 · United States
NIGMS NIH HHS · R01 GM079357-01A1 · United States
External Links
PubMed source DOI: 10.1016/j.bmc.2007.10.021 PMC Full Text View journal details
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