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

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• 作者：Beow Keat Yap ; Eleanor W. W. Leung ; Hiromasa Yagi ; Charles A. Galea ; Sandeep Chhabra ; David K. Chalmers ; Sandra E. Nicholson ; Philip E. Thompson ; Raymond S. Norton
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 28, 2014
• 年：2014
• 卷：57
• 期：16
• 页码：7006-7015
• 全文大小：485K
• ISSN：1520-4804

文摘

The protein SPSB2 mediates proteosomal degradation of inducible nitric oxide synthase (iNOS). Inhibitors of SPSB2鈥搃NOS 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鈥搃NOS 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鈥搃NOS interactions by the cyclic peptide. Furthermore, its solution structure closely matched (backbone rmsd 1.21 脜) 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.