Inhibition of batroxobin, a serine proteinase from Bothrops snake venom, by derivatives of benzamidine.
Benzamidine derivatives which are competitive inhibitors of trypsin-like serine proteinases also inhibited the enzymatic activity of batroxobin, a thrombin-like snake venom proteinase. Structure-activity relationships showed that primary amides of 4-amidinophenyl-alpha-aminobutyric acid have pronounced, relatively selective antibatroxobin activity. Identical effects were found on batroxobin isolated from the venoms of Bothrops atrox or Bothrops moojeni. Esters containing a benzamidine moiety acylated the active centre serine hydroxyl of either batroxobin, however, the inhibition was temporary. Such compounds, especially 4-amidinophenyl esters of substituted benzoic acids, are a particularly useful tool for designing acyl-batroxobin intermediates with different deacylation rates. With 4-nitrophenyl 4'-guanidinobenzoate, the acyl enzyme was formed so rapidly that titration of the active site of batroxobin was possible. Irreversible inhibition of batroxobin was caused only by the selective thrombin inhibitor D-Phe-Pro-ArgCH2Cl.
D000215:Acylation; D000578:Amidines / Q000494:pharmacology*; D012103:Batroxobin / Q000037:antagonists & inhibitors*; D001550:Benzamidines / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D006639:Histidine / Q000378:metabolism; D006868:Hydrolysis; D007700:Kinetics; D010447:Peptide Hydrolases; D011480:Protease Inhibitors; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors
D000578:Amidines; D001550:Benzamidines; D011480:Protease Inhibitors; D006639:Histidine; D010447:Peptide Hydrolases; D012103:Batroxobin; D013917:Thrombin