Development of MDL 28,050, a small stable antithrombin agent based on a functional domain of the leech protein, hirudin.
MDL 28,050 is a decapeptide antithrombin agent that inhibits alpha-thrombin-induced fibrin clot formation by binding to a non-catalytic site on alpha-thrombin. It is the result of chemical and structural optimization of a functional domain of the leech anticoagulant, hirudin. In contrast to the contention that the polyanionic nature of this C-terminal functional domain governs its interaction with alpha-thrombin, systematic study of this region has shown the importance of the lipophilic residues for providing the functionality necessary for potent binding to alpha-thrombin. The development of MDL 28,050 and other effective antithrombin agents are outlined through the description of the structure-activity relationships (SAR) for these peptides. These peptides are effective in a variety of in vitro and in vivo models of thrombosis.
Krstenansky
J L
JL
Merrell Dow Research Institute, Cincinnati, OH 45215.
Broersma
R J
RJ
Owen
T J
TJ
Payne
M H
MH
Yates
M T
MT
Mao
S J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D001780:Blood Coagulation Tests; D002863:Chromogenic Compounds / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism; D006629:Hirudins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000378:metabolism
D000991:Antithrombins; D002863:Chromogenic Compounds; D004151:Dipeptides; D006629:Hirudins; D009842:Oligopeptides; C064762:MDL 28050; C021129:S 2238; D013917:Thrombin