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.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

Synthetic C-terminal variants of hirudin54-65 were tested for antithrombin activity in human plasma; replacing Gln65 with hydrophilic L-amino acids or amino alcohols largely preserved potency, while carboxamide derivatives and deletion of residue 65 reduced it.

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