Journal article
Redox-stable cyclic peptide inhibitors of the SPSB2-iNOS interaction
BK Yap, JR Harjani, EWW Leung, SE Nicholson, MJ Scanlon, DK Chalmers, PE Thompson, JB Baell, RS Norton
FEBS Letters | WILEY-BLACKWELL | Published : 2016
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 19F 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.
Grants
Awarded by Australian National Health Medical Research Council (NHMRC)
Awarded by NHMRC IRIISS grant
Funding Acknowledgements
BKY is the recipient of the Academic Staff Training Scheme Fellowship of Universiti Sains Malaysia. RSN and JBB acknowledge fellowship support from the National Health and Medical Research Council of Australia. This study was supported in part by the Australian National Health Medical Research Council (NHMRC) (Grants 1022693 and 1016647), as well as an NHMRC IRIISS grant 361646 and a Victorian State Government Operational Infrastructure Scheme grant. The authors declare no competing financial interest.