A NOVEL DRUG LEAD TO ANTIHYPERTENSIVE AGENT FROM Tityus serrulatus VENOM

VERANO-BRAGA T. (1,2), SILVA D.M.R. (4), SANTOS C.F.F. (4), BEMQUERER M.P. (2,3), SANTOS R.A.S. (4), BOUGIS P.E. (5), MARTIN-EAUCLAIRE M.F. (5), DE LIMA M.E. (1,2) , PIMENTA A.M.C. (1,2)

(1) Núcleo de Biomoléculas, (2) LVTA and (3) Lab. de Enzimologia e Físico-Química de Proteínas, Depto. de Bioquímica e Imunologia e (4) Lab. de Hipertensão, Depto. de Fisiologia e Biofísica, ICB, UFMG, Belo Horizonte, Brazil.

(5) CNRS-FRE 2738, Ingénierie des Protéines, Université de la Méditerranée, UMR6560, IFR Jean Roche, 13916 Marseille, France

Facilities in using micro-scale analytical techniques have led to a novel approach to prospect bioactive molecules in animal venoms. By this approach, we were able to find a new structural family of peptides in the venom of Tityus serrulatus, named TsHptP (T. serrulatus Hypotensive Peptides). Structurally, these are random-coiled linear peptides, ranging from 2.5 to 3 KDa and have a similar bradykinin-potentiating peptide (BPP) amino acid signature. TsHpt-I, a member of this peptide family, was able to potentiate the hypotensive effects of bradykinin (BK) in normotensive rats. To optimize the pharmacokinetics and the stability of TsHpt-I, few synthetic analogs were constructed using the TsHpt-I as a template. These analogs held the BK-potentiating effect. A relevant hypotensive action, which is independent on BK, was observed in all of these analogs, indicating that they are themselves hypotensive agents. We used hypertensive rats strains to study this hypotensive effect and it has been shown that these analogs induces a strong and long-lasting hypotensive effect. To evaluate this action, we examined the vasorelaxation effect of aortic rings derived from male Wistar rats. The analogs were able to induce ± 20% of vasorelaxation (10-7 M). One of these analogs was orally administrated in SHR rats and was able to reduce the blood pressure, indicating that it is stable and can be absorbed in the gastrointestinal tract. Beside these peptides have a similar amino acid sequence with the classical BPPs, some differences in the primary structure (data not shown) may be crucial to the new pharmacological effects observed in this peptides.

KEY WORDS: Bradykinin Potentiating Peptide, Tityus serrulatus, hypotensive peptides

FINANCIAL SUPPORT: CNPq; FAPEMIG; FINEP

CORRESPONDENCE TO: Adriano Pimenta, E-mail: apimenta@icb.ufmg.br