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

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18 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

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