A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent

Beow Keat Yap, Eleanor Wai Wai Leung, Hiromasa Yagi, Charles Galea, Sandeep Chhabra, David Kenneth Chalmers, Sandra E Nicholson, Philip Thompson, Raymond Stanley Norton

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2-iNOS interaction may prolong the lifetime of iNOS and thereby enhance the killing of persistent pathogens. We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key sequence motif mediating the SPSB2-iNOS interaction, which binds to the iNOS binding site on SPSB2 with a Kd of 4.4 nM, as shown by SPR, [ 1H,15N]-HSQC, and 19F NMR. An in vitro assay on macrophage cell lysates showed complete inhibition of SPSB2-iNOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 ?) that of the SPSB2-bound linear DINNN peptide. The designed peptide was resistant to degradation by the proteases pepsin, trypsin, and chymotrypsin and stable in human plasma. This cyclic peptide exemplifies potentially a new class of anti-infective agents that acts on the host innate response, thereby avoiding the development of pathogen resistance.
Original languageEnglish
Pages (from-to)7006 - 7015
Number of pages10
JournalJournal of Medicinal Chemistry
Volume57
Issue number16
DOIs
Publication statusPublished - 2014

Cite this

Yap, Beow Keat ; Leung, Eleanor Wai Wai ; Yagi, Hiromasa ; Galea, Charles ; Chhabra, Sandeep ; Chalmers, David Kenneth ; Nicholson, Sandra E ; Thompson, Philip ; Norton, Raymond Stanley. / A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 16. pp. 7006 - 7015.
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abstract = "The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2-iNOS interaction may prolong the lifetime of iNOS and thereby enhance the killing of persistent pathogens. We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key sequence motif mediating the SPSB2-iNOS interaction, which binds to the iNOS binding site on SPSB2 with a Kd of 4.4 nM, as shown by SPR, [ 1H,15N]-HSQC, and 19F NMR. An in vitro assay on macrophage cell lysates showed complete inhibition of SPSB2-iNOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 ?) that of the SPSB2-bound linear DINNN peptide. The designed peptide was resistant to degradation by the proteases pepsin, trypsin, and chymotrypsin and stable in human plasma. This cyclic peptide exemplifies potentially a new class of anti-infective agents that acts on the host innate response, thereby avoiding the development of pathogen resistance.",
author = "Yap, {Beow Keat} and Leung, {Eleanor Wai Wai} and Hiromasa Yagi and Charles Galea and Sandeep Chhabra and Chalmers, {David Kenneth} and Nicholson, {Sandra E} and Philip Thompson and Norton, {Raymond Stanley}",
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A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent. / Yap, Beow Keat; Leung, Eleanor Wai Wai; Yagi, Hiromasa; Galea, Charles; Chhabra, Sandeep; Chalmers, David Kenneth; Nicholson, Sandra E; Thompson, Philip; Norton, Raymond Stanley.

In: Journal of Medicinal Chemistry, Vol. 57, No. 16, 2014, p. 7006 - 7015.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent

AU - Yap, Beow Keat

AU - Leung, Eleanor Wai Wai

AU - Yagi, Hiromasa

AU - Galea, Charles

AU - Chhabra, Sandeep

AU - Chalmers, David Kenneth

AU - Nicholson, Sandra E

AU - Thompson, Philip

AU - Norton, Raymond Stanley

PY - 2014

Y1 - 2014

N2 - The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2-iNOS interaction may prolong the lifetime of iNOS and thereby enhance the killing of persistent pathogens. We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key sequence motif mediating the SPSB2-iNOS interaction, which binds to the iNOS binding site on SPSB2 with a Kd of 4.4 nM, as shown by SPR, [ 1H,15N]-HSQC, and 19F NMR. An in vitro assay on macrophage cell lysates showed complete inhibition of SPSB2-iNOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 ?) that of the SPSB2-bound linear DINNN peptide. The designed peptide was resistant to degradation by the proteases pepsin, trypsin, and chymotrypsin and stable in human plasma. This cyclic peptide exemplifies potentially a new class of anti-infective agents that acts on the host innate response, thereby avoiding the development of pathogen resistance.

AB - The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2-iNOS interaction may prolong the lifetime of iNOS and thereby enhance the killing of persistent pathogens. We have designed a cyclic peptide, Ac-c[CVDINNNC]-NH2, containing the key sequence motif mediating the SPSB2-iNOS interaction, which binds to the iNOS binding site on SPSB2 with a Kd of 4.4 nM, as shown by SPR, [ 1H,15N]-HSQC, and 19F NMR. An in vitro assay on macrophage cell lysates showed complete inhibition of SPSB2-iNOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 ?) that of the SPSB2-bound linear DINNN peptide. The designed peptide was resistant to degradation by the proteases pepsin, trypsin, and chymotrypsin and stable in human plasma. This cyclic peptide exemplifies potentially a new class of anti-infective agents that acts on the host innate response, thereby avoiding the development of pathogen resistance.

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U2 - 10.1021/jm500596j

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