Structure-function relationships of hirulog peptide interactions with thrombin.
Using hirudin as a model, a novel class of bivalent thrombin inhibitors has been designed and characterized (Maraganore et al. (1990) Biochemistry 29, 7095-7101). These peptides, designated 'hirulogs', interact with both thrombin's catalytic center and its anion-binding exosite for fibrinogen recognition. In order to investigate structure-activity relationships in hirulog peptides, a number of peptide and peptidomimetic derivatives with alterations in catalytic-site binding and anion-binding exosite binding moieties were prepared. Replacements or modifications in the catalytic site and exosite binding moieties were achieved with the consequences of maintaining or improving antithrombin activity. In addition to showing improved affinity for thrombin, some derivatives with Ki's in the sub-nanomolar range showed increased anticoagulant activities. These findings highlight the versatility of hirulog peptides in their bivalent interactions with thrombin.
Bourdon
P
P
Biogen Inc., Cambridge, MA 02142.
Jablonski
J A
JA
Chao
B H
BH
Maraganore
J M
JM
D000595:Amino Acid Sequence; D000838:Anions; D001665:Binding Sites; D001667:Binding, Competitive; D006629:Hirudins / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007455:Iodine; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D013431:Sulfates; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014443:Tyrosine / Q000737:chemistry
D000838:Anions; D006629:Hirudins; D013431:Sulfates; D014443:Tyrosine; D007455:Iodine; D013917:Thrombin