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A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent

SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated and targeted for degradation. Inhibition of this interaction increases iNOS levels, and consequently cellular nitric oxide (NO) concent...

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Main Authors: Mohd Shariff, Fairolniza, Sadek, Maiada M., Barlow, Nicholas, Leung, Eleanor W.W., Noonan, Billy J. Williams, Yap, Beow Keat, Davies, Tom T. Caradoc, Nicholsan, Sandra E., Chalmers, David K., Thompson, Philip E., Law, Ruby H. P., Norton, Raymond S.
Format: Article
Language:English
Published: American Chemical Society 2018
Online Access:http://psasir.upm.edu.my/id/eprint/72901/1/INOS.pdf
http://psasir.upm.edu.my/id/eprint/72901/
https://pubs.acs.org/doi/10.1021/acschembio.8b00561
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spelling my.upm.eprints.729012020-12-01T21:32:50Z http://psasir.upm.edu.my/id/eprint/72901/ A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent Mohd Shariff, Fairolniza Sadek, Maiada M. Barlow, Nicholas Leung, Eleanor W.W. Noonan, Billy J. Williams Yap, Beow Keat Davies, Tom T. Caradoc Nicholsan, Sandra E. Chalmers, David K. Thompson, Philip E. Law, Ruby H. P. Norton, Raymond S. SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated and targeted for degradation. Inhibition of this interaction increases iNOS levels, and consequently cellular nitric oxide (NO) concentrations, and has been proposed as a potential strategy for killing intracellular pathogens. We previously described two DINNN-containing cyclic peptides (CP1 and CP2) as potent inhibitors of the murine SPSB-iNOS interaction. In this study, we report the crystal structures of human SPSB4 bound to CP1 and CP2 and human SPSB2 bound to CP2. We then used these structures to design a new inhibitor in which an intramolecular hydrogen bond was replaced with a hydrocarbon linkage to form a smaller macrocycle while maintaining the bound geometry of CP2 observed in the crystal structures. This resulting pentapeptide SPSB-iNOS inhibitor (CP3) has a reduced macrocycle ring size, fewer nonbinding residues, and includes additional conformational constraints. CP3 has a greater affinity for SBSB2 ( KD = 7 nM as determined by surface plasmon resonance) and strongly inhibits the SPSB2-iNOS interaction in macrophage cell lysates. We have also determined the crystal structure of CP3 in complex with human SPSB2, which reveals the structural basis for the increased potency of CP3 and validates the original design. American Chemical Society 2018 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/72901/1/INOS.pdf Mohd Shariff, Fairolniza and Sadek, Maiada M. and Barlow, Nicholas and Leung, Eleanor W.W. and Noonan, Billy J. Williams and Yap, Beow Keat and Davies, Tom T. Caradoc and Nicholsan, Sandra E. and Chalmers, David K. and Thompson, Philip E. and Law, Ruby H. P. and Norton, Raymond S. (2018) A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent. ACS Chemical Biology, 13 (10). 2930 - 2938. ISSN 1554-8937; ESSN: 1554-8929 https://pubs.acs.org/doi/10.1021/acschembio.8b00561 10.1021/acschembio.8b00561
institution Universiti Putra Malaysia
building UPM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Putra Malaysia
content_source UPM Institutional Repository
url_provider http://psasir.upm.edu.my/
language English
description SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4 interact with inducible nitric oxide synthase (iNOS), causing the iNOS to be polyubiquitinated and targeted for degradation. Inhibition of this interaction increases iNOS levels, and consequently cellular nitric oxide (NO) concentrations, and has been proposed as a potential strategy for killing intracellular pathogens. We previously described two DINNN-containing cyclic peptides (CP1 and CP2) as potent inhibitors of the murine SPSB-iNOS interaction. In this study, we report the crystal structures of human SPSB4 bound to CP1 and CP2 and human SPSB2 bound to CP2. We then used these structures to design a new inhibitor in which an intramolecular hydrogen bond was replaced with a hydrocarbon linkage to form a smaller macrocycle while maintaining the bound geometry of CP2 observed in the crystal structures. This resulting pentapeptide SPSB-iNOS inhibitor (CP3) has a reduced macrocycle ring size, fewer nonbinding residues, and includes additional conformational constraints. CP3 has a greater affinity for SBSB2 ( KD = 7 nM as determined by surface plasmon resonance) and strongly inhibits the SPSB2-iNOS interaction in macrophage cell lysates. We have also determined the crystal structure of CP3 in complex with human SPSB2, which reveals the structural basis for the increased potency of CP3 and validates the original design.
format Article
author Mohd Shariff, Fairolniza
Sadek, Maiada M.
Barlow, Nicholas
Leung, Eleanor W.W.
Noonan, Billy J. Williams
Yap, Beow Keat
Davies, Tom T. Caradoc
Nicholsan, Sandra E.
Chalmers, David K.
Thompson, Philip E.
Law, Ruby H. P.
Norton, Raymond S.
spellingShingle Mohd Shariff, Fairolniza
Sadek, Maiada M.
Barlow, Nicholas
Leung, Eleanor W.W.
Noonan, Billy J. Williams
Yap, Beow Keat
Davies, Tom T. Caradoc
Nicholsan, Sandra E.
Chalmers, David K.
Thompson, Philip E.
Law, Ruby H. P.
Norton, Raymond S.
A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent
author_facet Mohd Shariff, Fairolniza
Sadek, Maiada M.
Barlow, Nicholas
Leung, Eleanor W.W.
Noonan, Billy J. Williams
Yap, Beow Keat
Davies, Tom T. Caradoc
Nicholsan, Sandra E.
Chalmers, David K.
Thompson, Philip E.
Law, Ruby H. P.
Norton, Raymond S.
author_sort Mohd Shariff, Fairolniza
title A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent
title_short A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent
title_full A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent
title_fullStr A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent
title_full_unstemmed A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent
title_sort cyclic peptide inhibitor of the inos–spsb protein–protein interaction as a potential anti-infective agent
publisher American Chemical Society
publishDate 2018
url http://psasir.upm.edu.my/id/eprint/72901/1/INOS.pdf
http://psasir.upm.edu.my/id/eprint/72901/
https://pubs.acs.org/doi/10.1021/acschembio.8b00561
_version_ 1687395148662571008
score 13.211869

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