Discovery of Novel Potential Reversible Peptidyl Arginine Deiminase Inhibitor

International Journal of Molecular Sciences

Piotr Mydel¹  Tomasz Kantyka¹  Ardita Aliko¹  Alicia Wong²  Marta Kamińska²  Joanna Kozieł²  Katherine Falkowski²  Danuta Bryzek²  Malgorzata Benedyk-Machaczka³  Ewa Bielecka³  Stanisław Malicki³ 

[1] Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway;Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland;Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Kraków, Poland;

关键词: PAD4;    inhibitor;    citrullination;    rheumatoid arthritis;    PPAD;    NETs;   

DOI  :  10.3390/ijms20092174

来源: DOAJ

【 摘 要 】

Citrullination, a posttranslational modification, is catalyzed by peptidylarginine deiminases (PADs), a unique family of enzymes that converts peptidyl-arginine to peptidyl-citrulline. Overexpression and/or increased PAD activity is observed in rheumatoid arthritis (RA), Alzheimer’s disease, multiple sclerosis, and cancer. Moreover, bacterial PADs, such as Porphyromonas gingivalis PAD (PPAD), may have a role in the pathogenesis of RA, indicating PADs as promising therapeutic targets. Herein, six novel compounds were examined as potential inhibitors of human PAD4 and PPAD, and compared to an irreversible PAD inhibitor, Cl-amidine. Four of the tested compounds (compounds 2, 3, 4, and 6) exhibited a micromolar-range inhibition potency against PAD4 and no effect against PPAD in the in vitro assays. Compound 4 was able to inhibit the PAD4-induced citrullination of H3 histone with higher efficiency than Cl-amidine. In conclusion, compound 4 was highly effective and presents a promising direction in the search for novel RA treatment strategies.

【 授权许可】

Unknown