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Abstract
The protein arginine deiminase 4 (PAD4) is a calcium-dependent enzyme, which catalyses the irreversible conversion of peptidyl-arginines into peptidyl-citrullines and plays an important role in several diseases such as in the rheumatoid arthritis, multiple sclerosis, Alzheimer’s disease, Creutzfeldt–Jacob’s disease and cancer. In this study, we report the inhibition profiles and computational docking toward the PAD4 enzyme of a series of 1,2,3-triazole peptidomimetic-based derivatives incorporating the β-phenylalanine and guanidine scaffolds. Several effective, low micromolar PAD4 inhibitors are reported in this study.
Acknowledgements
The authors thank Dr. Andrea Brancale for his assistance on the elaboration of the molecular modeling calculation.
Declaration of interest
The authors confirm that this article content has no conflict of interest.
I. K., T. D., A. S., C. T. S. and F. C. are grateful to an EU FP7 project, Gums & Joints, for financial support (Grant agreement: HEALTH-F2-2010-261460). M. S. and N. P. gratefully acknowledge the “Fondazione Banco di Sardegna” for its partial financial support.
Notes
iK05 is defined as the concentration of calcium corresponding to half of the maximalmenzyme activity.
iiiThe antibody-based kit for PAD4 activity measurements was obtained from Modiquest Research, AJ Nijmegen, The Netherlands (Cat. no. MQ-17.101-96) and provides a 96-well microplate in which the bottom of each reaction well is coated with arginine containing peptides as the substrate for PAD4.
iiiMolecular Operating Environment (MOE 2009.10). Chemical Computing Group, Inc. Montreal, Quebec, Canada.