title: Novel inhibitors of protein arginine deiminase with potential activity in multiple sclerosis animal model.
abstract: In multiple sclerosis (MS), myelin basic protein (MBP), critical for the maintenance of myelin compaction and protecting against degradation, is known to contain concentrations of the noncoded amino acid, "citrulline", in abnormal proportions. Peptidyl arginine deiminase (PAD) catalyzes the post-translational citrullination of proteins via the deimination of Arg residues. In the central nervous system, specifically PAD2 and PAD4, are the enzymes responsible for the citrullination. We used in silico screening of commercial libraries to find small molecules that would reversibly inhibit PAD4. An initial set of 10 diverse compounds was selected from the screen, and from these compounds, 3, 4, 6, and 8 showed promising inhibitory activities against PAD4 with Ki in the range of 115-153 μM. Compound 4 was selected to partake in an in vivo MOG EAE mouse model study to evaluate its effect in MS-like conditions. Results from the 24 day pilot mouse study showed an improved clinical outcome for mice being administered compound 4 compared to the control group. In brain, 4 treated mice showed a clear reduction in the CD3 +ve T cells. These results suggest that compound 4 may have potential utility and confirmed that noncovalent inhibitors of PAD enzymes can be developed as potential agents targeting MS pathology.
authors: Center for Molecular Design and Preformulations, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada.
authors: Lianhu
authors: L
authors: Wei
authors: Ewa
authors: E
authors: Wasilewski
authors: Sai Kumar
authors: SK
authors: Chakka
authors: Angelica M
authors: AM
authors: Bello
authors: Mario A
authors: MA
authors: Moscarello
authors: Lakshmi P
authors: LP
authors: Kotra
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D020134:Catalytic Domain; D003198:Computer Simulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000188:drug therapy*; D010865:Pilot Projects; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D017252:CD3 Complex; D007093:Imidazoles; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D054852:Small Molecule Libraries; D013844:Thiazoles; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; C552151:peptidylarginine deiminase 4, mouse