C-terminal peptide alcohol, acid and amide analogs of desulfato hirudin54-65 as antithrombin agents.
Analogs of the antithrombin peptide hirudin54-65 with C-terminal modifications have been synthesized in order to examine the requirements for alpha-thrombin inhibition. The C-terminal residue, Gln65, could be replaced with L-amino acids or amino alcohols with neutral or charged hydrophilic side chains without greatly affecting the peptide's antithrombin potency as determined by inhibition of thrombin-induced clot formation in human plasma in vitro. Derivatives with D- or L-amino carboxamides at position 65 had significantly reduced potency, but still retained activity. Deletion of residue 65 with conversion of residue 64 to the amide or alcohol derivative resulted in a three-fold loss of potency. In addition to these results the solid-phase synthesis of peptide alcohols via direct displacement of p-nitrobenzhydrylideneisonitroso resin attached peptides with the desired C-terminal amino alcohol is reported.
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
J L
JL
Krstenansky
M H
MH
Payne
T J
TJ
Owen
M T
MT
Yates
S J
SJ
Mao
D000143:Acids; D000438:Alcohols; D000577:Amides; D000991:Antithrombins; D005260:Female; D005337:Fibrin / Q000037:antagonists & inhibitors; D006629:Hirudins / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D010455:Peptides / Q000138:chemical synthesis
D000143:Acids; D000438:Alcohols; D000577:Amides; D000991:Antithrombins; D006629:Hirudins; D010455:Peptides; D005337:Fibrin