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Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4)


Citation

Teo, Chian Ying and Tejo, Bimo Ario and Leow, Adam Thean Chor and Salleh, Abu Bakar and Abdul Rahman, Mohd Basyaruddin (2017) Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4). Chemical Biology & Drug Design, 90 (6). pp. 1134-1146. ISSN 1747-0277; ESSN: 1747-0285

Abstract

Protein arginine deiminase type IV (PAD4) is responsible for the posttranslational conversion of peptidylarginine to peptidylcitrulline. Citrullinated protein is the autoantigen in rheumatoid arthritis, and therefore, PAD4 is currently a promising therapeutic target for the disease. Recently, we reported the importance of the furan ring in the structure of PAD4 inhibitors. In this study, the furan ring was incorporated into peptides to act as the “warhead” of the inhibitors for PAD4. IC50 studies showed that the furan-containing peptide-based inhibitors were able to inhibit PAD4 to a better extent than the furan-containing small molecules that were previously reported. The best peptide-based inhibitor inhibited PAD4 reversibly and competitively with an IC50 value of 243.2 ± 2.4 μm. NMR spectroscopy and NMR-restrained molecular dynamic simulations revealed that the peptide-based inhibitor had a random structure. Molecular docking studies showed that the peptide-based inhibitor entered the binding site and interacted with the essential amino acids involved in the catalytic activity. The peptide-based inhibitor could be further developed into a therapeutic drug for rheumatoid arthritis.


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Additional Metadata

Item Type: Article
Divisions: Faculty of Biotechnology and Biomolecular Sciences
Faculty of Science
DOI Number: https://doi.org/10.1111/cbdd.13033
Publisher: John Wiley & Sons A/S
Keywords: Drug design; Peptide-based inhibitors; Protein arginine deiminase IV; Rheumatoid arthritis
Depositing User: Nabilah Mustapa
Date Deposited: 15 Mar 2018 04:43
Last Modified: 15 Mar 2018 04:43
Altmetrics: http://www.altmetric.com/details.php?domain=psasir.upm.edu.my&doi=10.1111/cbdd.13033
URI: http://psasir.upm.edu.my/id/eprint/59664
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