Estudos bioquímicos, farmacológicos e de minimização da estrutura do peptídeo TsHpT-I isolado do veneno do escorpião Tityus serrulatus

Abstract

Scorpion venom is a rich source of biologically active peptides that act in different systems, such as nervous and cardiovascular. A new structural family of peptides was found in the venom of the Brazilian yellow scorpion Tityus serrulatus. This family, named TsHpTP (Tityus serrulatus HypoTensive Peptides), has a typical bradykinin-potentiating peptide (BPP) amino acid signature at its C-terminal extremity. TsHpT-I, a 2722 Da peptide, was able to potentiate the hypotensive effects of bradykinin (BK) in normotensive rats. It was observed that this peptide has two carboxypeptidase Y cleavage-resistance sites at its C-terminal portion (Lys17-Glu18 e Pro23-Pro24). Therefore, two synthetic analogs were constructed using TsHpT-I C-terminal as template (TsHpT17-25 and TsHpTac17-25am, which is acetylated at N-terminal and amidated at C-terminal). The bradykinin-potentiating effect was maintained in these two analogs suggesting that the C-terminal portion of the native peptide is important to the pharmacological activity. Also, a relevant hypotensive effect, which is independent on BK, was observed in all of these peptides, indicating that these peptides are themselves hypotensive agents. To study this hypotensive effect, TsHpT17-25 was tested in hypertensive SHR (Spontaneous Hypertensive Rats) and TGR (Transgenic Rats) rat strains and it has been shown that this peptide induce a strong and long-lasting hypotensive effect. Interestingly, this peptide was also able to slow down the heart rate (HR) of these animals. The mode of action of these peptides is yet to be solved, but it seems that angiotensin converting enzyme - a well known BPP target - is not the primary target. Instead, preliminary data using CHO cells with transfected B2 receptor - carried out in confocal microscopy - has shown that these peptides are able to potentiate the nitric oxide release induced by BK, although the molecular mechanism of this potentiation is not clear yet.