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

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)696-704
Number of pages9
JournalFEBS Letters
Volume590
Issue number6
DOIs
Publication statusPublished - 1 Mar 2016

Keywords

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

Cite this

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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.",
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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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journal = "FEBS Letters",
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Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction. / Yap, Beow Keat; Harjani, Jitendra R.; Leung, Eleanor W W; Nicholson, Sandra E; Scanlon, Martin J.; Chalmers, David K.; Thompson, Philip E.; Baell, Jonathan B.; Norton, Raymond S.

In: FEBS Letters, Vol. 590, No. 6, 01.03.2016, p. 696-704.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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.

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Y1 - 2016/3/1

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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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