A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent
- Yap, BK; Leung, EW; Yagi, H; Galea, CA; Chhabra, S; Chalmers, DK; Nicholson, SE; Thompson, PE; Norton, RS;
Publication Year 2014-08-28, Volume 57, Issue #16, Page 7006-15
- Journal Title
- J Med Chem
- Publication Type
- Journal Article
- 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, [(1)H,(15)N]-HSQC, and (19)F 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 A) 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.
- WEHI Research Division(s)
- Publisher's Version
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Creation Date: 2014-10-27 03:57:36Last Modified: 2014-11-28 09:27:56