title: A potent cyclic peptide targeting SPSB2 protein as a potential anti-infective agent.
abstract: 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 Kd of 4.4 nM, as shown by SPR, [(1)H,(15)N]-HSQC, and (19)F 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.
authors: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville 3052, Victoria, Australia.
authors: Beow Keat
authors: BK
authors: Yap
authors: Eleanor W W
authors: EW
authors: Leung
authors: Hiromasa
authors: H
authors: Yagi
authors: Charles A
authors: CA
authors: Galea
authors: Sandeep
authors: S
authors: Chhabra
authors: David K
authors: DK
authors: Chalmers
authors: Sandra E
authors: SE
authors: Nicholson
authors: Philip E
authors: PE
authors: Thompson
authors: Raymond S
authors: RS
authors: Norton
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D058990:Molecular Targeted Therapy; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D055550:Protein Stability; D021381:Protein Transport; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D000890:Anti-Infective Agents; D010456:Peptides, Cyclic; D050826:Suppressor of Cytokine Signaling Proteins; D052247:Nitric Oxide Synthase Type II