Design, synthesis, and characterization of cyclic peptidomimetics of the inducible nitric oxide synthase binding epitope that disrupt the protein-protein interaction involving SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2 and inducible nitric oxide synthase

Jitendra R. Harjani, Beow Keat Yap, Eleanor W W Leung, Andrew Lucke, Sandra E. Nicholson, Martin J. Scanlon, David K. Chalmers, Philip E. Thompson, Raymond S. Norton, Jonathan B. Baell

Research output: Contribution to journalArticleResearchpeer-review

Abstract

SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2-deficient macrophages have been found to exhibit prolonged expression of inducible nitric oxide synthase (iNOS) and enhanced killing of persistent pathogens, suggesting that inhibitors of the SPSB2-iNOS interaction have potential as novel anti-infectives. In this study, we describe the design, synthesis, and characterization of cyclic peptidomimetic inhibitors of the SPSB2-iNOS interaction constrained by organic linkers to improve stability and druggability. SPR, ITC, and 19F NMR analyses revealed that the most potent cyclic peptidomimetic bound to the iNOS binding site of SPSB2 with low nanomolar affinity (KD 29 nM), a 10-fold improvement over that of the linear peptide DINNN (KD 318 nM), and showed strong inhibition of SPSB2-iNOS interaction in macrophage cell lysates. This study exemplifies a novel approach to cyclize a Type II β-turn linear peptide and provides a foundation for future development of this group of inhibitors as new anti-infectives.
Original languageEnglish
Pages (from-to)5799-5809
Number of pages11
JournalJournal of Medicinal Chemistry
Volume59
Issue number12
DOIs
Publication statusPublished - 23 Jun 2016

Cite this

@article{6575fb198b624796aae4d7193fe74445,
title = "Design, synthesis, and characterization of cyclic peptidomimetics of the inducible nitric oxide synthase binding epitope that disrupt the protein-protein interaction involving SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2 and inducible nitric oxide synthase",
abstract = "SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2-deficient macrophages have been found to exhibit prolonged expression of inducible nitric oxide synthase (iNOS) and enhanced killing of persistent pathogens, suggesting that inhibitors of the SPSB2-iNOS interaction have potential as novel anti-infectives. In this study, we describe the design, synthesis, and characterization of cyclic peptidomimetic inhibitors of the SPSB2-iNOS interaction constrained by organic linkers to improve stability and druggability. SPR, ITC, and 19F NMR analyses revealed that the most potent cyclic peptidomimetic bound to the iNOS binding site of SPSB2 with low nanomolar affinity (KD 29 nM), a 10-fold improvement over that of the linear peptide DINNN (KD 318 nM), and showed strong inhibition of SPSB2-iNOS interaction in macrophage cell lysates. This study exemplifies a novel approach to cyclize a Type II β-turn linear peptide and provides a foundation for future development of this group of inhibitors as new anti-infectives.",
author = "Harjani, {Jitendra R.} and Yap, {Beow Keat} and Leung, {Eleanor W W} and Andrew Lucke and Nicholson, {Sandra E.} and Scanlon, {Martin J.} and Chalmers, {David K.} and Thompson, {Philip E.} and Norton, {Raymond S.} and Baell, {Jonathan B.}",
year = "2016",
month = "6",
day = "23",
doi = "10.1021/acs.jmedchem.6b00386",
language = "English",
volume = "59",
pages = "5799--5809",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "12",

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TY - JOUR

T1 - Design, synthesis, and characterization of cyclic peptidomimetics of the inducible nitric oxide synthase binding epitope that disrupt the protein-protein interaction involving SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2 and inducible nitric oxide synthase

AU - Harjani, Jitendra R.

AU - Yap, Beow Keat

AU - Leung, Eleanor W W

AU - Lucke, Andrew

AU - Nicholson, Sandra E.

AU - Scanlon, Martin J.

AU - Chalmers, David K.

AU - Thompson, Philip E.

AU - Norton, Raymond S.

AU - Baell, Jonathan B.

PY - 2016/6/23

Y1 - 2016/6/23

N2 - SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2-deficient macrophages have been found to exhibit prolonged expression of inducible nitric oxide synthase (iNOS) and enhanced killing of persistent pathogens, suggesting that inhibitors of the SPSB2-iNOS interaction have potential as novel anti-infectives. In this study, we describe the design, synthesis, and characterization of cyclic peptidomimetic inhibitors of the SPSB2-iNOS interaction constrained by organic linkers to improve stability and druggability. SPR, ITC, and 19F NMR analyses revealed that the most potent cyclic peptidomimetic bound to the iNOS binding site of SPSB2 with low nanomolar affinity (KD 29 nM), a 10-fold improvement over that of the linear peptide DINNN (KD 318 nM), and showed strong inhibition of SPSB2-iNOS interaction in macrophage cell lysates. This study exemplifies a novel approach to cyclize a Type II β-turn linear peptide and provides a foundation for future development of this group of inhibitors as new anti-infectives.

AB - SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2-deficient macrophages have been found to exhibit prolonged expression of inducible nitric oxide synthase (iNOS) and enhanced killing of persistent pathogens, suggesting that inhibitors of the SPSB2-iNOS interaction have potential as novel anti-infectives. In this study, we describe the design, synthesis, and characterization of cyclic peptidomimetic inhibitors of the SPSB2-iNOS interaction constrained by organic linkers to improve stability and druggability. SPR, ITC, and 19F NMR analyses revealed that the most potent cyclic peptidomimetic bound to the iNOS binding site of SPSB2 with low nanomolar affinity (KD 29 nM), a 10-fold improvement over that of the linear peptide DINNN (KD 318 nM), and showed strong inhibition of SPSB2-iNOS interaction in macrophage cell lysates. This study exemplifies a novel approach to cyclize a Type II β-turn linear peptide and provides a foundation for future development of this group of inhibitors as new anti-infectives.

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U2 - 10.1021/acs.jmedchem.6b00386

DO - 10.1021/acs.jmedchem.6b00386

M3 - Article

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SP - 5799

EP - 5809

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -