Inhibition of batroxobin, a serine proteinase from Bothrops snake venom, by derivatives of benzamidine

Toxicon. 1986;24(6):585-95. doi: 10.1016/0041-0101(86)90179-0.

Abstract

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.

MeSH terms

  • Acylation
  • Amidines / pharmacology*
  • Batroxobin / antagonists & inhibitors*
  • Benzamidines / pharmacology*
  • Binding Sites / drug effects
  • Histidine / metabolism
  • Hydrolysis
  • Kinetics
  • Peptide Hydrolases
  • Protease Inhibitors*
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors

Substances

  • Amidines
  • Benzamidines
  • Protease Inhibitors
  • Histidine
  • Peptide Hydrolases
  • Batroxobin
  • Thrombin