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Coagulation Factor XIIIa Inhibitor Tridegin: On the Role of Disulfide Bonds for Folding, Stability, and Function.
Bäuml, Charlotte A; Schmitz, Thomas; Paul George, Ajay Abisheck; Sudarsanam, Monica; Hardes, Kornelia; Steinmetzer, Torsten; Holle, Lori A; Wolberg, Alisa S; Pötzsch, Bernd; Oldenburg, Johannes; Biswas, Arijit; Imhof, Diana.
Afiliación
  • Bäuml CA; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute , University of Bonn , An der Immenburg 4 , 53121 Bonn , Germany.
  • Schmitz T; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute , University of Bonn , An der Immenburg 4 , 53121 Bonn , Germany.
  • Paul George AA; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute , University of Bonn , An der Immenburg 4 , 53121 Bonn , Germany.
  • Sudarsanam M; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute , University of Bonn , An der Immenburg 4 , 53121 Bonn , Germany.
  • Hardes K; Institute of Pharmaceutical Chemistry , Philipps University of Marburg , Marbacher Weg 6 , 35032 Marburg , Germany.
  • Steinmetzer T; Institute of Pharmaceutical Chemistry , Philipps University of Marburg , Marbacher Weg 6 , 35032 Marburg , Germany.
  • Holle LA; Department of Pathology and Laboratory Medicine , University of North Carolina at Chapel Hill , 819 Brinkhous-Bullitt Building , Chapel Hill , North Carolina 27599 , United States.
  • Wolberg AS; Department of Pathology and Laboratory Medicine , University of North Carolina at Chapel Hill , 819 Brinkhous-Bullitt Building , Chapel Hill , North Carolina 27599 , United States.
  • Pötzsch B; Institute of Experimental Hematology and Transfusion Medicine , University Hospital Bonn , Sigmund-Freud-Str. 25 , 53127 Bonn , Germany.
  • Oldenburg J; Institute of Experimental Hematology and Transfusion Medicine , University Hospital Bonn , Sigmund-Freud-Str. 25 , 53127 Bonn , Germany.
  • Biswas A; Institute of Experimental Hematology and Transfusion Medicine , University Hospital Bonn , Sigmund-Freud-Str. 25 , 53127 Bonn , Germany.
  • Imhof D; Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute , University of Bonn , An der Immenburg 4 , 53121 Bonn , Germany.
J Med Chem ; 62(7): 3513-3523, 2019 04 11.
Article en En | MEDLINE | ID: mdl-30852892
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas y Péptidos Salivales / Factor XIIIa / Disulfuros Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas y Péptidos Salivales / Factor XIIIa / Disulfuros Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Alemania