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

Beow Keat Yap; Jitendra R Harjani; Eleanor W W Leung; Sandra E Nicholson; Martin J Scanlon; David K Chalmers; Philip E Thompson; Jonathan B Baell; Raymond S Norton

doi:10.1002/1873-3468.12115

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

FEBS Lett. 2016 Mar;590(6):696-704. doi: 10.1002/1873-3468.12115. Epub 2016 Mar 6.

Authors

Beow Keat Yap¹, Jitendra R Harjani¹, Eleanor W W Leung¹, Sandra E Nicholson^{2

3}, Martin J Scanlon¹, David K Chalmers¹, Philip E Thompson¹, Jonathan B Baell¹, Raymond S Norton¹

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Anti-Infective Agents / chemical synthesis
Anti-Infective Agents / chemistry
Anti-Infective Agents / pharmacology
DNA-Binding Proteins / antagonists & inhibitors*
DNA-Binding Proteins / chemistry
DNA-Binding Proteins / metabolism
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
In Vitro Techniques
Kinetics
Macrophages / drug effects
Macrophages / metabolism
Magnetic Resonance Spectroscopy
Mice
Mice, Inbred C57BL
Models, Molecular
Molecular Structure
Nitric Oxide Synthase Type II / antagonists & inhibitors*
Nitric Oxide Synthase Type II / chemistry
Nitric Oxide Synthase Type II / metabolism
Oxidation-Reduction
Peptides, Cyclic / chemical synthesis
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Protein Interaction Domains and Motifs
Protein Stability
Surface Plasmon Resonance

Substances

Anti-Infective Agents
DNA-Binding Proteins
Enzyme Inhibitors
Peptides, Cyclic
SSB-2 protein, mouse
Nitric Oxide Synthase Type II
Nos2 protein, mouse