Design, synthesis, and characterization of cyclic peptidomimetics of the inducible nitric oxide synthase binding epitope that disrupt the protein-protein interaction involving SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2 and inducible nitric oxide synthase
Details
Publication Year 2016-06-23, Volume 59, Issue #12, Page 5799-809
Journal Title
J Med Chem
Publication Type
Journal Article
Abstract
SPRY domain-containing suppressor of cytokine signaling box protein (SPSB) 2-deficient macrophages have been found to exhibit prolonged expression of inducible nitric oxide synthase (iNOS) and enhanced killing of persistent pathogens, suggesting that inhibitors of the SPSB2-iNOS interaction have potential as novel anti-infectives. In this study, we describe the design, synthesis, and characterization of cyclic peptidomimetic inhibitors of the SPSB2-iNOS interaction constrained by organic linkers to improve stability and druggability. SPR, ITC, and (19)F NMR analyses revealed that the most potent cyclic peptidomimetic bound to the iNOS binding site of SPSB2 with low nanomolar affinity (KD 29 nM), a 10-fold improvement over that of the linear peptide DINNN (KD 318 nM), and showed strong inhibition of SPSB2-iNOS interaction in macrophage cell lysates. This study exemplifies a novel approach to cyclize a Type II beta-turn linear peptide and provides a foundation for future development of this group of inhibitors as new anti-infectives.
Publisher
ACS
WEHI Research Division(s)
Inflammation
PubMed ID
27214043
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2016-10-04 09:29:24
Last Modified: 2016-10-04 11:28:04
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