Insights into cardiovascular effects of proline-rich oligopeptide (Bj-PRO-10c) revealed by structure-activity analyses: dissociation of antihypertensive and bradycardic effects

Insights into cardiovascular effects of proline-rich oligopeptide (Bj-PRO-10c) revealed by structure-activity analyses: dissociation of antihypertensive and bradycardic effects

Author Paschoal, Juliana F. B. Autor UNIFESP Google Scholar
Yamaguchi, Juliana Autor UNIFESP Google Scholar
Miranda, Jose R. R. Autor UNIFESP Google Scholar
Carretero, Gustavo Google Scholar
Melo, Robson L. Google Scholar
Santos, Robson A. S. Google Scholar
Xavier, Carlos H. Google Scholar
Schreier, Shirley Google Scholar
Camargo, Antonio C. M. Google Scholar
Ianzer, Danielle Google Scholar
Institution Butantan Inst
Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Universidade Federal de Minas Gerais (UFMG)
Universidade Federal de Goiás (UFG)
Abstract We have previously reported that the proline-rich decapeptide from Bothrops jararaca (Bj-PRO-10c) causes potent and sustained antihypertensive and bradycardic effects in SHR. These activities are independent of ACE inhibition. in the present study, we used the Ala-scan approach to evaluate the importance of each amino acid within the sequence of Bj-PRO-10c (Pyr(1)-Asn(2)-Trp(3)-Pro(4)-His(5)-Pro(6)-Gln(7)-Ile(8)-Pro(9)-Pro(10)). the antihypertensive and bradycardic effects of the analogues Bj-PRO-10c Ala(3), Bj-PRO-10c Ala(7), Bj-PRO-10c Ala(8) were similar to those of Bj-PRO-10c, whereas the analogues Bj-PRO-10c Ala(2), Bj-PRO-10c Ala(4), Bj-PRO-10c Ala(5), Bj-PRO-10c Ala(9), and Bj-PRO-10c Ala(10) kept the antihypertensive activity and lost bradycardic activity considerably. in contrast, Bj-PRO-10c Ala(1) and Bj-PRO-10c Ala(6) were unable to provoke any cardiovascular activity. in summary, we demonstrated that (1) the Pyr(1) and Pro(6) residues are essential for both, the antihypertensive and bradycardic effects of Bj-PRO-10c; (2) Ala-scan approach allowed dissociating blood pressure reduction and bradycardic effects. Conformational properties of the peptides were examined by means of circular dichroism (CD) spectroscopy. the different Ala-scan analogues caused either an increase or decrease in the type II polyproline helix content compared to Bj-PRO-10c. the complete loss of activity of the Pro(6) -> Ala(6) mutant is probably due to the fact that in the parent peptide the His(5)-Pro(6) bond can exist in the cis configuration, which could correspond to the conformation of this bond in the bound state. Current data support the Bj-PRO-10c as a promising leader prototype to develop new agents to treat cardiovascular diseases and its co-morbidities.
Keywords Proline-rich oligopeptide
Hypertension
Ala-scan approach
Arterial pressure
Heart rate
Circular dicroism
Language English
Date 2014-02-01
Published in Amino Acids. Wien: Springer Wien, v. 46, n. 2, p. 401-413, 2014.
ISSN 0939-4451 (Sherpa/Romeo, impact factor)
Publisher Springer
Extent 401-413
Origin http://dx.doi.org/10.1007/s00726-013-1630-x
Access rights Closed access
Type Article
Web of Science ID WOS:000330957300016
URI http://repositorio.unifesp.br/handle/11600/37360

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