VASOPEPTIDASE INHIBITION WITH SELETIVITY FOR THE ACTIVE SITE AT THE C-DOMAIN OF ACE BY BRADYKININ POTENTIATING PEPTIDES FROM Bothrops jararaca VENOM

Ianzer, D.A.(1), Portaro, F.C.V.(1), Paula, R.D.(2), Silva, C.A.(1), Gorrão, S.S.(1), Prezoto, B.C.(1), Nascimento, N.(3), Cotton, J.(4), Dive, V.(4), Santos, R.A.S.(2), Camargo, A.C.M.(1)

(1)Center of Applied Toxinology (CAT, CEPID-FAPESP), Departamento de Bioquímica e Biofísica, Instituto Butantan, SP, (2)Departamento de Fisiologia, ICB, UFMG, (3)Laboratório de Biologia Molecular, IPEN, (4)CEA, Départment d´Ingénierie et d´Estudes des Protéines (DIEP) Yvette Cedex, France. 

Venoms produced by snakes are, in general, constituted by several proteases and peptides that act as toxins. The bradykinin-potentiating peptides (BPPs) are constituents of the serpents toxins and represent the first natural inhibitors of ACE discovered. The ACE enzyme possesses two catalytic sites, at the N-terminus and C-terminus domains. Although both active sites are able to convert angiotensin I into angiotensin II and inactivate Bradykinin, the site at the C-domain seems to be more specific. Moreover, another enzyme, the neutral endopeptidase (NEP) inactivates bradykinin and natriuretic peptides. Together, both enzymes of the endothelial cells are designated vasopeptidases. Thus, the development of combined inhibitors for the vasopeptidases (VPIs) is of importance for the treatment of cardiovascular dysfunction. In this work, we studied three activities concerning the BPPs: 1) Inhibition of the vasopeptidases ACE and NEP, 2) The bradykinin potentiating effect using isolated guinea pig ileum assays and 3) Effect of the BPPs on the arterial pressure of anaesthetized rat. The results obtained in the kinetic studies showed that the BPPs act as NEP inhibitors and some of these peptides are selective inhibitors for the C-terminus domain of ACE. About these results, BPP-Xc is one of the most interesting peptides, since it is able to block both the ACE C-domain and the NEP activities. This peptide also potentiated the bradykinin activity and showed the best result in potentiating the bradykinin hypotensive effect in vivo assays. In addition, preliminary studies in mices showed that the BPP-Xc was still intact in urine after i.p. injections. We concluded the BPP-Xc can be considered a model for the development of a potent drug for treatment of the human hypertension.

Supported by: FAPESP, CNPq and FINEP

CORRESPONDENCE TO:

DanielleAlves Ianzer, Rua Francisco Estácio Fortes, 136, São Paulo, SP, CEP: 01233-060, Brasil, Email: daianzer.biof@infar.epm.br