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

作者：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^*

来源：Journal of Medicinal Chemistry, 2014, 57(16): 7006-7015.

DOI：10.1021/jm500596j

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, [H-1,N-15]-HSQC, and F-19 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 angstrom) 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.

• 出版日期2014-8-28
• 单位河北医科大学