Design, synthesis and antithrombin activity for conformationally restricted analogs of peptide anticoagulants based on the C-terminal region of the leech peptide, hirudin.
Synthetic peptides cyclized via disulfide linkages have been synthesized as conformationally restricted analogs of a novel class of antithrombotic peptides that inhibit fibrinogen cleavage by binding to a non-enzymatic site on thrombin. Several conformational models for these inhibitors have been considered and cyclic analogs were synthesized to test their validity. Compounds designed on an alpha-helical model yielded several cyclic analogs that retained antithrombin activity. [D-Cys58, Cys61]-hirudin54-65, 5, and [D-Cys60, Cys63]-hirudin54-65, 6, had IC50 values of 26 and 30 microM, respectively, in an in vitro clot assay compared with a value of 3.7 microM for the linear hirudin54-65.
Krstenansky
J L
JL
Merrell Dow Research Institute, Cincinnati, OH 45215.
Owen
T J
TJ
Yates
M T
MT
Mao
S J
SJ
D000595:Amino Acid Sequence; D000925:Anticoagulants; D000991:Antithrombins; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D015195:Drug Design; D006629:Hirudins; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000925:Anticoagulants; D000991:Antithrombins; D006629:Hirudins; D009842:Oligopeptides