Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction

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

doi:10.1002/1873-3468.12115

Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction

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

Medicinal Chemistry

Research output: Contribution to journal › Article › Research › peer-review

17 Citations (Scopus)

Abstract

SPSB2 mediates the proteasomal degradation of iNOS. Inhibitors of SPSB2-iNOS interaction are expected to prolong iNOS lifetime and thereby enhance killing of persistent pathogens. Here, we describe the synthesis and characterization of two redox-stable cyclized peptides containing the DINNN motif required for SPSB2 binding. Both analogues bind with low nanomolar affinity to the iNOS binding site on SPSB, as determined by SPR and 19F NMR, and efficiently displace full-length iNOS from binding to SPSB2 in macrophage cell lysates. These peptides provide a foundation for future development of redox-stable, potent ligands for SPSB proteins as a potential novel class of anti-infectives.

Original language	English
Pages (from-to)	696-704
Number of pages	9
Journal	FEBS Letters
Volume	590
Issue number	6
DOIs	https://doi.org/10.1002/1873-3468.12115
Publication status	Published - 1 Mar 2016

Keywords

anti-infective
cyclic peptide
inducible nitric oxide synthase
redox-stable
SPRY domain of the SOCS-box protein 2

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10.1002/1873-3468.12115

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title = "Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction",

abstract = "SPSB2 mediates the proteasomal degradation of iNOS. Inhibitors of SPSB2-iNOS interaction are expected to prolong iNOS lifetime and thereby enhance killing of persistent pathogens. Here, we describe the synthesis and characterization of two redox-stable cyclized peptides containing the DINNN motif required for SPSB2 binding. Both analogues bind with low nanomolar affinity to the iNOS binding site on SPSB, as determined by SPR and 19F NMR, and efficiently displace full-length iNOS from binding to SPSB2 in macrophage cell lysates. These peptides provide a foundation for future development of redox-stable, potent ligands for SPSB proteins as a potential novel class of anti-infectives.",

keywords = "anti-infective, cyclic peptide, inducible nitric oxide synthase, redox-stable, SPRY domain of the SOCS-box protein 2",

author = "Yap, {Beow Keat} and Harjani, {Jitendra R.} and Leung, {Eleanor W W} and Nicholson, {Sandra E} and Scanlon, {Martin J.} and Chalmers, {David K.} and Thompson, {Philip E.} and Baell, {Jonathan B.} and Norton, {Raymond S.}",

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doi = "10.1002/1873-3468.12115",

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T1 - Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction

AU - Yap, Beow Keat

AU - Harjani, Jitendra R.

AU - Leung, Eleanor W W

AU - Nicholson, Sandra E

AU - Scanlon, Martin J.

AU - Chalmers, David K.

AU - Thompson, Philip E.

AU - Baell, Jonathan B.

AU - Norton, Raymond S.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - SPSB2 mediates the proteasomal degradation of iNOS. Inhibitors of SPSB2-iNOS interaction are expected to prolong iNOS lifetime and thereby enhance killing of persistent pathogens. Here, we describe the synthesis and characterization of two redox-stable cyclized peptides containing the DINNN motif required for SPSB2 binding. Both analogues bind with low nanomolar affinity to the iNOS binding site on SPSB, as determined by SPR and 19F NMR, and efficiently displace full-length iNOS from binding to SPSB2 in macrophage cell lysates. These peptides provide a foundation for future development of redox-stable, potent ligands for SPSB proteins as a potential novel class of anti-infectives.

AB - SPSB2 mediates the proteasomal degradation of iNOS. Inhibitors of SPSB2-iNOS interaction are expected to prolong iNOS lifetime and thereby enhance killing of persistent pathogens. Here, we describe the synthesis and characterization of two redox-stable cyclized peptides containing the DINNN motif required for SPSB2 binding. Both analogues bind with low nanomolar affinity to the iNOS binding site on SPSB, as determined by SPR and 19F NMR, and efficiently displace full-length iNOS from binding to SPSB2 in macrophage cell lysates. These peptides provide a foundation for future development of redox-stable, potent ligands for SPSB proteins as a potential novel class of anti-infectives.

KW - anti-infective

KW - cyclic peptide

KW - inducible nitric oxide synthase

KW - redox-stable

KW - SPRY domain of the SOCS-box protein 2

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JO - FEBS Letters

JF - FEBS Letters

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Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction

Abstract

Keywords

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Inhibitors of Inducible Nitric Oxide Synthase (iNOS) Regulation as a Basis for Novel Anti-Infective Agents

NHMRC Research Fellowship

NHMRC Research Fellowship

Cite this

Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction

Abstract

Keywords

Access to Document

Other files and links

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Inhibitors of Inducible Nitric Oxide Synthase (iNOS) Regulation as a Basis for Novel Anti-Infective Agents

NHMRC Research Fellowship

NHMRC Research Fellowship

Cite this