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Title: Insights into cardiovascular effects of proline-rich oligopeptide (Bj-PRO-10c) revealed by structure-activity analyses: dissociation of antihypertensive and bradycardic effects
Authors: Paschoal, Juliana F. B. [UNIFESP]
Yamaguchi, Juliana [UNIFESP]
Miranda, Jose R. R. [UNIFESP]
Carretero, Gustavo
Melo, Robson L.
Santos, Robson A. S.
Xavier, Carlos H.
Schreier, Shirley
Camargo, Antonio C. M.
Ianzer, Danielle
Butantan Inst
Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Universidade Federal de Minas Gerais (UFMG)
Universidade Federal de Goiás (UFG)
Keywords: Proline-rich oligopeptide
Ala-scan approach
Arterial pressure
Heart rate
Circular dicroism
Issue Date: 1-Feb-2014
Publisher: Springer
Citation: Amino Acids. Wien: Springer Wien, v. 46, n. 2, p. 401-413, 2014.
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.
ISSN: 0939-4451
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