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

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• 作者：Jitendra R. Harjani ; Beow Keat Yap ; Eleanor W. W. Leung ; Andrew Lucke ; Sandra E. Nicholson ; Martin J. Scanlon ; David K. Chalmers ; Philip E. Thompson ; Raymond S. Norton ; Jonathan B. Baell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 23, 2016
• 年：2016
• 卷：59
• 期：12
• 页码：5799-5809
• 全文大小：512K
• 年卷期：0
• ISSN：1520-4804

文摘

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 ¹⁹F NMR analyses revealed that the most potent cyclic peptidomimetic bound to the iNOS binding site of SPSB2 with low nanomolar affinity (K_D 29 nM), a 10-fold improvement over that of the linear peptide DINNN (K_D 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 β-turn linear peptide and provides a foundation for future development of this group of inhibitors as new anti-infectives.