Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides

Ahmad Nadzirin, Izzuddin and Chor, Adam Leow Thean and Salleh, Abu Bakar and Abdul Rahman, Mohd Basyaruddin and Tejo, Bimo Ario (2021) Discovery of new inhibitor for the Protein Arginine Deiminase Type 4 (PAD4) by Rational Design of α-Enolase-derived Peptides. Computational Biology and Chemistry, 92. pp. 1-9. ISSN 1476-9271

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Abstract

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting about 0.5–1.0% of the world population. Protein arginine deiminase type 4 (PAD4) is believed to be responsible for the occurrence of RA by catalyzing citrullination of proteins. The citrullinated proteins act as autoantigens by stimulating an immune response. Citrullinated α-enolase has been identified as one of the autoantigens for RA. Hence, α-enolase serves as a suitable template for design of potential peptide inhibitors against PAD4. The binding affinity of α-enolase-derived peptides and PAD4 was virtually determined using PatchDock and HADDOCK docking programs. Synthesis of the designed peptides was performed using a solid phase peptide synthesis method. The inhibitory potential of each peptide was determined experimentally by PAD4 inhibition assay and IC50 measurement. PAD4 assay data show that the N-P2 peptide is the most favourable substrate among all peptides. Further modification of N-P2 by changing the Arg residue to canavanine [P2 (Cav)] rendered it an inhibitor against PAD4 by reducing the PAD4 activity to 35% with IC50 1.39 mM. We conclude that P2 (Cav) is a potential inhibitor against PAD4 and can serve as a starting point for the development of even more potent inhibitors.

Item Type:	Article (Journal)
Uncontrolled Keywords:	Drug design, PAD4, Peptide inhibitor, Rheumatoid arthritis
Subjects:	Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology R Medicine > RM Therapeutics. Pharmacology > RM300 Drugs and their action
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Allied Health Sciences Kulliyyah of Allied Health Sciences > Department of Biomedical Science (Effective:1st July 2011)
Depositing User:	Dr. Izzuddin Ahmad Nadzirin
Date Deposited:	06 Oct 2021 14:48
Last Modified:	06 Oct 2021 14:48
URI:	http://irep.iium.edu.my/id/eprint/92776

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