Bothrops jararaca

In the first phase of their research, Squibb tested a short-chain peptide isolated from the venom of the viper Bothrops jararaca, with which Vane was working in the laboratory, in human volunteers and showed that it did, indeed, inhibit the conversion of angiotensin I to angiotensin II after intravenous injection. The peptide was also shown to reduce blood pressure in patients when injected. Since the vast majority of peptides cannot be absorbed from the GI tract, Squibb scientists set out to prepare a nonpeptide compound that could be used orally and manufactured at acceptable cost. The design of a true peptidomimetic that became orally active had not been accomplished at that time. Squibb then carried out... 

S American pit viper, Bothrops jararaca (Wied, 1824), Serpentes, Reptilia... 

It is a aqueous solution of haemocoagulase isolated from venom of Bothrops jararaca and B. atorox containing normal saline. It is indicated in primary and secondary postoperative internal and external haemorrhage. 

Enzyme Inhibitors from the Venom of Bothrops Jararaca Isolation, Elucidation of Structure, and Synthesis. Biochemistry. 1971,10, 4033 4039. 

Ferreira s interest in the physiology of bradykinin led him in the early 1960s to search for substances that would inhibit its in vivo inactivation. The venom of the Brazilian arrowhead viper Bothrops jararaca generates bradykinin in plasma, and Ferreira discovered that the venom itself contained substances capable of potentiating bradykinin-induced contractions of isolated guinea pig ileum. He and Rocha e Silva called the active fraction of this venom the bradykinin-potentiating factor (BPF) (75). 

Ferreira, S.H., Bartelt, C., and Greene, F.J. 1970. Isolation of bradikinin potentiating peptides from Bothrops jararaca venom. Biochemistry 9, 2583-2593. 

Ondetti, M.A., Willimans, N.J., Sabo, E.F., Plusces, J., Weaver, E.R., and Kocy, O. 1971. Angiotensin-converting enzyme inhibitors from the venom of Bothrops jararaca. Isolation, elucidation of structure and synthesis. Biochemistry 19, 4033-4039. 

Jarariiagin, a snake venom fi om Bothrops jararaca, contains a metalloproteinase that cleaves the p, subunit (GPIIa) of the receptor complex, resulting in an inhibition of platelet adhesion to collagen" as well as an inhibition of early platelet signalling events in response to collagen, as demonstrated in the loss of pp72(syk) phosphorylation. 

Ferreira, S. H. A bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca. Br. J. Pharmacol. Chemother. 1965,24, 163-169. 

An inhibitor of the converting enzyme would therefore constitute a good candidate for the treatment of patients suffering from hypertension. The first substance developed in this sense has been teprotide, a nonapeptide presenting an identical sequence to that of some peptides isolated in 1965 by Ferreira from the venom of Bothrops jararaca, a Brazilian viper (Figure 6.21). 

Usami, Y., Fujimura, Y., Miura, S., Shima, H., Yoshida, E., Yoshioka, A., Hirano, K., Suzuki, M., and Titani, K. (1994). A 28-kDa-protein with disintegrinlike structure (jararhagin-C) purified from Bothrops jararaca venom inhibits collagen- and ADP- induced platelet aggregation. Biochem. Biophys. Res. Commun. 207 331-339. 

This synthetic product was derived from studies reported in 1965 by Ferreira, where he demonstrated that there were principles in the venom of the pit viper, Bothrops jararaca, which inhibited the degradation of the nonape-tide, bradykinin. Subsequently, workers at Squibb ... 

Jararaca, Bothrops jararaca, 850 Water snake, Natrix spp., 715 Western ribbon snake, Thamnophis proximos, 298... 

Several peptides isolated from the venom of the South American snake Bothrops jararaca are potent ACE inhibitors and were briefly used for the treatment of hypertension, but were soon superseded by surprisingly simple molecules with high inhibitory effect. At the Squibb Institute for Medical Research in Princeton, New Jersey, Miguel A. Ondetti (Plate 32) recognized that ACE is similar in its substrate specificity to the well studied protease car-boxypeptidase A. He designed, therefore, molecules that should fit into the active site of ACE (presumably similar to the active site of carboxypeptidase A) and form complexes with the enzyme. The dipeptide , 2-D-methyl-3-mercapto-propionyl-L-proline, captopril [7] strongly associated with the enzyme and... 

The bradykinin potentiating effect of a series of peptides present in the venom of the South American poisonous snake Bothrops jararaca has already been mentioned in connection with the inhibition of the angiotensin converting enzyme (cf. p. 183) [33]. These proline rich peptides... 

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