| Literature DB >> 30852892 |
Charlotte A Bäuml1, Thomas Schmitz1, Ajay Abisheck Paul George1, Monica Sudarsanam1, Kornelia Hardes2, Torsten Steinmetzer2, Lori A Holle3, Alisa S Wolberg3, Bernd Pötzsch4, Johannes Oldenburg4, Arijit Biswas4, Diana Imhof1.
Abstract
Tridegin is a potent and specific 66mer peptide inhibitor of coagulation factor XIIIa with six cysteines involved in three disulfide bonds. Three of the 15 possible 3-disulfide-bonded isomers have been identified, which share a bridge between cysteines 19 and 25. We synthesized the three possible 2-disulfide-bonded analogues using a targeted protecting group strategy to investigate the impact of the C19-C25 bond on tridegin's folding, stability, and function. The FXIIIa inhibitory activity of the analogues was retained, which was shown by in vitro fluorogenic activity and whole blood clotting assays. Molecular dynamics simulations of wild-type tridegin and the analogues as well as molecular docking studies with FXIIIa were performed to elucidate the impact of the C19-C25 bond on conformational stability and binding mode. The strategy of selectively reducing disulfide bonds to facilitate large-scale synthesis, while retaining the functionality of disulfide-bonded peptides, has been demonstrated with our present study.Entities:
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Year: 2019 PMID： 30852892 PMCID： PMC6650289 DOI： 10.1021/acs.jmedchem.8b01982
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446