In:
European Journal of Biochemistry, Wiley, Vol. 265, No. 2 ( 1999-10), p. 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 hirulog contains an N α ‐(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 α ‐(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 γ‐amino butyric acid 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 n m ), while BZA‐2 hirulog was characterized as a slow, tight binding inhibitor of thrombin ( K i = 0.29 ± 0.08 p m ). 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 α‐thrombin was solved and confirmed the expected bivalent binding mode.
Type of Medium:
Online Resource
ISSN:
0014-2956
,
1432-1033
DOI:
10.1046/j.1432-1327.1999.00742.x
Language:
English
Publisher:
Wiley
Publication Date:
1999
detail.hit.zdb_id:
1398347-7
detail.hit.zdb_id:
2172518-4
SSG:
12
