Discovery of new inhibitor for the protein arginine deiminase type 4 (PAD4) by rational design of α-enolase-derived peptides. (June 2021)

• Record Type: Journal Article
• Authors: Ahmad Nadzirin, Izzuddin; Chor, Adam Leow Thean; Salleh, Abu Bakar; Rahman, Mohd Basyaruddin Abdul; Tejo, Bimo A.
• Is Part Of: Computational biology and chemistry. Volume 92(2021)
• Publication Date: 2021-06
• Subjects: ACPA anti-citrullinated protein antibodies -- Arg arginine -- BAEE N-α-benzoyl-l-arginine ethyl ester -- BSA bovine serum albumin -- Cit citrulline -- DIEA diisopropylethylamine -- DMARD disease modifying anti-rheumatic drug -- DMF dimethylformamide -- Fmoc 9-fluorenylmethyloxycarbonyl -- HADDOCK high ambiguity driven biomolecular docking -- HCTU 2-(6-Chloro-1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethylaminium hexafluorophosphate -- HPLC high performance liquid chromatography -- IC50 half maximal inhibitory concentration -- IL-15 interleukin-15 -- LC/MS liquid chromatography/mass spectroscopy -- Lys lysine -- MT1-MMP membrane type 1 matrix metalloproteinase -- MTX methotrexate -- NMR nuclear magnetic resonance -- NSAID non-steroidal anti inflammatory drug -- PAD4 protein arginine deiminase type 4 -- PDB protein data bank -- RA rheumatoid arthritis -- RMSD root mean square deviation -- sOPEP coarse-grained energy score -- SPPS solid phase peptide synthesis -- TFA trifluoroacetic acid -- XRC X-ray crystallography; Drug design -- PAD4 -- Peptide inhibitor -- Rheumatoid arthritis; Chemistry -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; Biochemistry -- Data processing; Biology -- Data processing; Molecular biology -- Data processing; Periodicals; Electronic journals; 542.85
• DOI: 10.1016/j.compbiolchem.2021.107487
• Languages: English
• ISSNs: 1476-9271

Abstract

Highlights: Protein arginine deiminase type 4 (PAD4) is identified as being responsible for pathogenesis of rheumatoid arthritis. PAD4 converts the arginine residue to citrulline in certain proteins, which subsequently act as autoantigens that stimulate antibody production. We discovered a peptide with a better inhibitory activity against PAD4 compared to existing PAD4 inhibitors such as MTX and streptomycin. Abstract: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting about 0.24 % 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.