A Potent Cyclic Peptide Targeting SPSB2 Protein as a Potential Anti-infective Agent

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 seque...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-08, Vol.57 (16), p.7006-7015
Main Authors: Yap, Beow Keat, Leung, Eleanor W. W, Yagi, Hiromasa, Galea, Charles A, Chhabra, Sandeep, Chalmers, David K, Nicholson, Sandra E, Thompson, Philip E, Norton, Raymond S
Format: Article
Language:English
Subjects:
Animals
Anti-Infective Agents - chemistry
Anti-Infective Agents - pharmacology
Binding Sites
Humans
Immunity, Innate - drug effects
Macrophages - drug effects
Macrophages - metabolism
Magnetic Resonance Spectroscopy
Mice
Molecular Targeted Therapy
Nitric Oxide Synthase Type II - metabolism
Peptides, Cyclic - blood
Peptides, Cyclic - chemistry
Peptides, Cyclic - metabolism
Peptides, Cyclic - pharmacology
Protein Conformation
Protein Stability
Protein Transport
Suppressor of Cytokine Signaling Proteins - chemistry
Suppressor of Cytokine Signaling Proteins - metabolism
Surface Plasmon Resonance
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Summary: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 K d 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 Å) 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm500596j