A synthetic polypeptide conjugate from a 42-residue polypeptide and salicylhydroxamic acid binds human myeloperoxidase with high affinity
2012 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 18, no 12, 731-739 p.Article in journal (Refereed) Published
Myeloperoxidase (MPO) is a 150 kD tetrameric heme protein consisting of two heavy chains and two light chains, which ispresent in neutrophils, white blood cells, at concentrations between 2% and 5% and plays an important role in the innateimmune system. The MPO concentration in serum or plasma has been shown to be linked to the risk for cardiovasculardiseases, and MPO is considered to be a high potential diagnostic biomarker. To develop a molecule that binds MPO,salicylhydroxamic acid (SHA), a substrate analog inhibitor of MPO with a KD=2uM, was conjugated to a designed set of42-residue polypeptide scaffolds via 9- and 11-carbon atom aliphatic spacers to form 20 different protein binder candidates,and their interactions with MPO were evaluated by surface plasmon resonance analysis. The polypeptide conjugate4C37L34C11SHA was found to bind to MPO with an affinity that could be estimated to have a dissociation constant of around400 pM, nearly four orders of magnitude higher than that of SHA. Inhibition of binding to MPO by free SHA was observed incompetition experiments demonstrating that the binding of the polypeptide conjugate is dominated by the interactions ofSHA with the heme cavity. Although still in the future, the discovery of these new synthetic binders for MPO suggests aroute to clinical diagnostic tests in vivo or in vitro, independent of antibodies.
Place, publisher, year, edition, pages
2012. Vol. 18, no 12, 731-739 p.
Organic Chemistry Other Chemistry Topics
IdentifiersURN: urn:nbn:se:uu:diva-183195DOI: 10.1002/psc.2459ISI: 000311053700003OAI: oai:DiVA.org:uu-183195DiVA: diva2:562096