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Titolo:
Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines
Autore:
Steinmetzer, T; Renatus, M; Kunzel, S; Eichinger, A; Bode, W; Wikstrom, P; Hauptmann, J; Sturzebecher, J;
Indirizzi:
Univ Jena, Inst Biochem & Biophys, D-07743 Jena, Germany Univ Jena Jena Germany D-07743 Biochem & Biophys, D-07743 Jena, Germany Max Planck Inst Biochem, D-8033 Martinsried, Germany Max Planck Inst Biochem Martinsried Germany D-8033 Martinsried, Germany Pentapharm Ltd, CH-4002 Basel, Switzerland Pentapharm Ltd Basel Switzerland CH-4002 Ltd, CH-4002 Basel, Switzerland Univ Jena, Zentrum Vaskulare Biol & Med, Erfurt, Germany Univ Jena Erfurt Germany Zentrum Vaskulare Biol & Med, Erfurt, Germany
Titolo Testata:
EUROPEAN JOURNAL OF BIOCHEMISTRY
fascicolo: 2, volume: 265, anno: 1999,
pagine: 598 - 605
SICI:
0014-2956(199910)265:2<598:DAEONB>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN ALPHA-THROMBIN; TRUE HIRUDIN MIMETICS; RAY CRYSTAL-STRUCTURE; BOVINE THROMBIN; RATIONAL DESIGN; COMPLEXES; 4-AMIDINOPHENYLALANINE; ACID; 3-AMIDINOPHENYLALANINE; BENZAMIDINE;
Keywords:
anticoagulants; bivalent inhibitor; enzyme kinetics; hirudin; thrombin;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
43
Recensione:
Indirizzi per estratti:
Indirizzo: Steinmetzer, T Univ Jena, Inst Biochem & Biophys, Philosophenweg 12, D-07743 Jena, Germany Univ Jena Philosophenweg 12 Jena Germany D-07743 , Germany
Citazione:
T. Steinmetzer et al., "Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines", EUR J BIOCH, 265(2), 1999, pp. 598-605

Abstract

Two bivalent thrombin inhibitors were synthesized, which consist of a benzamidine-based active-site-blocking segment, a fibrinogen recognition exosite inhibitor and a peptidic linker connecting these fragments. BZA-1 hirulogcontains an N-alpha-(2-naphthylsulfonyl)-S-3-amidinophenylalanyl-isonipecotic acid residue connected via the carboxyl group to the linker segment. The active-site-directed moiety of BZA-2 hirulog [N-alpha-(2-naphthylsulfonyl-glutamyl)-R-4-amidinophenylalanyl-piperidide] was coupled to the linker via the side chain of the glutamic acid. Both BZA-hirulogs contain almost identical linker-exo site inhibitor parts, except for the substitution of a glycine as the first linker residue in BZA-1 hirulog by a gamma-amino butyricacid in BZA-2 hirulog, thus increasing flexibility and linker length by two additional atoms. BZA-1 hirulog showed moderate potency (K-i = 0.50 +/- 0.14 nM), while BZA-2 hirulog was characterized as a slow, tight binding inhibitor of thrombin (K-i = 0.29 +/- 0.08 pM). The stability in human plasma of both analogs was strongly improved compared with hirulog-1. For BZA-2 hirulog a significantly reduced plasma clearance was observed after intravenous injection in rats compared with BZA-1 hirulog and hirulog-1. The X-ray structure of the BZA-2 hirulog in complex with human alpha-thrombin was solved and confirmed the expected bivalent binding mode.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/07/20 alle ore 22:15:49