A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent
Details
Publication Year 2014-08-28, Volume 57, Issue #16, Page 7006-15
Journal Title
J Med Chem
Publication Type
Journal Article
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, [(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.
Publisher
ACS
WEHI Research Division(s)
Inflammation
Publisher's Version
https://doi.org/10.1021/jm500596j
NHMRC Grants
NHMRC/1022693 NHMRC/1016647
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2014-10-27 03:57:36
Last Modified: 2014-11-28 09:27:56
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