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Redox‐stable cyclic peptide inhibitors of the SPSB2–iNOS interaction
Author(s) -
Yap Beow Keat,
Harjani Jitendra R.,
Leung Eleanor W. W.,
Nicholson Sandra E.,
Scanlon Martin J.,
Chalmers David K.,
Thompson Philip E.,
Baell Jonathan B.,
Norton Raymond S.
Publication year - 2016
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12115
Subject(s) - redox , chemistry , peptide , cyclic peptide , biochemistry , biophysics , stereochemistry , combinatorial chemistry , biology , organic chemistry
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.