2. Academic Validation
  3. Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction

Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction

  • FEBS Lett. 2016 Mar;590(6):696-704. doi: 10.1002/1873-3468.12115.
Beow Keat Yap 1,  Jitendra R Harjani 1,  Eleanor W W Leung 1,  Sandra E Nicholson 2 3,  Martin J Scanlon 1,  David K Chalmers 1,  Philip E Thompson 1,  Jonathan B Baell 1,  Raymond S Norton 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic., Australia.
  • 2 The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.
  • 3 The Department of Medical Biology, University of Melbourne, Parkville, Vic., Australia.
PMID: 26921848 DOI: 10.1002/1873-3468.12115
Abstract

SPSB2 mediates the proteasomal degradation of iNOS. Inhibitors of SPSB2-iNOS interaction are expected to prolong iNOS lifetime and thereby enhance killing of persistent pathogens. Here, we describe the synthesis and characterization of two redox-stable cyclized Peptides containing the DINNN motif required for SPSB2 binding. Both analogues bind with low nanomolar affinity to the iNOS binding site on SPSB, as determined by SPR and (19)F NMR, and efficiently displace full-length iNOS from binding to SPSB2 in macrophage cell lysates. These Peptides provide a foundation for future development of redox-stable, potent ligands for SPSB proteins as a potential novel class of anti-infectives.

Keywords

SPRY domain of the SOCS-box protein 2; anti-infective; cyclic peptide; inducible nitric oxide synthase; redox-stable.

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