title: Synthesis and functional characterization of tridegin and its analogues: inhibitors and substrates of factor XIIIa.
abstract: Tridegin, a 66-mer peptide isolated from the leech Haementeria ghilianii, is a potent inhibitor of the coagulation factor XIIIa. This paper describes the chemical synthesis of tridegin by two different strategies--solid-phase assembly and native chemical ligation--both followed by oxidation in solution phase. Tridegin and truncated analogues were examined for their activity and revealed a particular importance of the C-terminal region of the parent peptide. Based on these studies a minimal sequence required for factor XIIIa inhibition could be identified. Our data revealed that the glutamine residue at position 52 (Q52) of tridegin most likely binds to the active site of factor XIIIa and was therefore suggested to react with the enzyme. The function of the N-terminal region is also discussed, as the isolated C-terminal segment of tridegin lost its inhibitory activity rapidly in the presence of factor XIIIa, whereas this was not the case for the full-length inhibitor.
authors.affiliation: Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn, Brühler Straße 7, 53119 Bonn, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Böhm
authors.forename: Toni
authors.initials: T
authors.lastname: Kühl
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hardes
authors.forename: Richard
authors.initials: R
authors.lastname: Coch
authors.forename: Christoph
authors.initials: C
authors.lastname: Arkona
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schlott
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
authors.forename: Diana
authors.initials: D
authors.lastname: Imhof
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D026122:Factor XIIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007865:Leeches / Q000378:metabolism; D008969:Molecular Sequence Data; D012471:Salivary Proteins and Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D012471:Salivary Proteins and Peptides; C106835:tridegin; D026122:Factor XIIIa