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

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 rep...

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Main Authors: Teo, Chian Ying, Tejo, Bimo Ario, Leow, Adam Thean Chor, Salleh, Abu Bakar, Abdul Rahman, Mohd Basyaruddin
Format: Article
Language:English
Published: John Wiley & Sons A/S 2017
Online Access:http://psasir.upm.edu.my/id/eprint/59664/1/Novel%20furan-containing%20peptide-based%20inhibitors%20of%20protein%20arginine%20deiminase%20type%20IV%20%28PAD4%29.pdf
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spelling oai:psasir.upm.edu.my:59664 http://psasir.upm.edu.my/id/eprint/59664/ Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4) Teo, Chian Ying Tejo, Bimo Ario Leow, Adam Thean Chor Salleh, Abu Bakar Abdul Rahman, Mohd Basyaruddin 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. John Wiley & Sons A/S 2017 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/59664/1/Novel%20furan-containing%20peptide-based%20inhibitors%20of%20protein%20arginine%20deiminase%20type%20IV%20%28PAD4%29.pdf 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 http://onlinelibrary.wiley.com/wol1/doi/10.1111/cbdd.13033/abstract 10.1111/cbdd.13033
institution UPM IR
collection UPM IR
language English
description 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.
format Article
author Teo, Chian Ying
Tejo, Bimo Ario
Leow, Adam Thean Chor
Salleh, Abu Bakar
Abdul Rahman, Mohd Basyaruddin
spellingShingle Teo, Chian Ying
Tejo, Bimo Ario
Leow, Adam Thean Chor
Salleh, Abu Bakar
Abdul Rahman, Mohd Basyaruddin
Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4)
author_facet Teo, Chian Ying
Tejo, Bimo Ario
Leow, Adam Thean Chor
Salleh, Abu Bakar
Abdul Rahman, Mohd Basyaruddin
author_sort Teo, Chian Ying
title Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4)
title_short Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4)
title_full Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4)
title_fullStr Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4)
title_full_unstemmed Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4)
title_sort novel furan-containing peptide-based inhibitors of protein arginine deiminase type iv (pad4)
publisher John Wiley & Sons A/S
publishDate 2017
url http://psasir.upm.edu.my/id/eprint/59664/1/Novel%20furan-containing%20peptide-based%20inhibitors%20of%20protein%20arginine%20deiminase%20type%20IV%20%28PAD4%29.pdf
_version_ 1782755993715736576
score 12.935284

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