A Potent Cyclic Peptide Targeting SPSB2 Protein as a Potential Anti-infective Agent
Beow Keat Yap, Eleanor WW Leung, Hiromasa Yagi, Charles A Galea, Sandeep Chhabra, David K Chalmers, Sandra E Nicholson, Philip E Thompson, Raymond S Norton
Journal of Medicinal Chemistry | AMER CHEMICAL SOC | Published : 2014
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 ..View full abstract
Awarded by Australian National Health Medical Research Council (NHMRC)
Awarded by NHMRC IRIISS
We thank Prof. Jonathan Baell, A/Prof. Martin Scanlon, and Dr. Mark Mulcair for helpful discussions, and Dr. David Shackleford for providing human plasma from the Australian Red Cross Blood Service. B.K.Y. is the recipient of an Academic Staff Training Scheme Fellowship of Universiti Sains Malaysia. R.S.N. and S.E.N. acknowledge fellowship support from the National Health and Medical Research Council of Australia. This study was supported 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.