Structure-function studies of BPP-BrachyNH(2) and synthetic analogues thereof with Angiotensin I-Converting Enzyme

Autor(es):Mostrar menos -

Arcanjo, Daniel D. R. ^{[1, 2]} ; Vasconcelos, Andreanne G. ^[1] ; Nascimento, Lucas A. ^{[3, 4]} ; Mafud, Ana Carolina ^{[5, 6]} ; Placido, Alexandra ^[7] ; Alves, Michel M. M. ^[2] ; Delerue-Matos, Cristina ^[7] ; Bemquerer, Marcelo P. ^[8] ; Vale, Nuno ^[9] ; Gomes, Paula ^[10] ; Oliveira, Eduardo B. ^[11] ; Lima, Francisco C. A. ^[4] ; Mascarenhas, Yvonne P. ^[5] ; Carvalho, Fernando Aecio A. ^[2] ; Simonsen, Ulf ^[12] ; Ramos, Ricardo M. c ^[3] ; Leite, Jose Roberto S. A. ^{[1, 13]}

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^[1] Univ Fed Piaui, UFPI, Nucleo Pesquisa Biodiversidade & Biotecnol BIOTEC, Campus Ministro Reis Velloso, BR-64202002 Parnaiba, PI - Brazil

^[2] Univ Fed Piaui, UFPI, NPPM, Campus Ministro Petronio Portella, SG-15, BR-64049550 Teresina, PI - Brazil

^[3] Inst Fed Piaui, Dept Informacao Ambiente Saude & Prod Alimenticia, LaPeSI, Lab Pesquisa Sistemas Informacao, Teresina - Brazil

^[4] Univ Estadual Piaui, Dept Quim, GQQCPF, Teresina - Brazil

^[5] Univ Sao Paulo, IFSC, Sao Carlos, SP - Brazil

^[6] Swiss Trop & Publ Hlth Inst, Dept Med Parasitol & Infect Biol, Basel - Switzerland

^[7] Inst Politecn Porto, Inst Super Engn, LAQV REQUIMTE, Rua Dr Antonio Bernardino de Almeida 431, P-4200072 Oporto - Portugal

^[8] EMBRAPA Recursos Genet & Biotecnol, PqEB, Parque Estacao Biol, Av W5 Norte Final, BR-70770917 Brasilia, DF - Brazil

^[9] Univ Porto, Fac Farm, Dept Ciencias Medicamento, UCIBIO REQUIMTE, Lab Farmacol, Rua Jorge Viterbo Ferreira 228, P-4050313 Oporto - Portugal

^[10] Univ Porto, Fac Ciencias, Dept Quim & Bioquim, LAQV REQUIMTE, Rua Campo Alegre 687, P-4169007 Oporto - Portugal

^[11] Univ Sao Paulo, Dept Bioquim & Imunol, BR-14096000 Sao Paulo - Brazil

^[12] Aarhus Univ, Dept Biomed Pulm & Cardiovasc Pharmacol, Aarhus - Denmark

^[13] Univ Brasilia, Area Morfol, Fac Med, UnB, Brasilia, DF - Brazil

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 139, p. 401-411, OCT 20 2017.
• Citações Web of Science: 1

Resumo

The vasoactive proline-rich oligopeptide termed BPP-BrachyNH(2) (H-WPPPKVSP-NH2) induces in vitro inhibitory activity of angiotensin I-converting enzyme (ACE) in rat blood serum. In the present study, the removal of N-terminal tryptophan or C-terminal proline from BPP-BrachyNH(2) was investigated in order to predict which structural components are important or required for interaction with ACE. Furthermore, the toxicological profile was assessed by in silico prediction and in vitro MIT assay. Two BPP-BrachyNH(2) analogues (des-Trp(1)-BPP-BrachyNH(2) and des-Pro(8)-BPP-BrachyNH(2)) were synthesized, and in vitro and in silico ACE inhibitory activity and toxicological profile were assessed. The des-Trp(1)-BPP-BrachyNH(2) and des-Pro(8)-BPP-BrachyNH(2) were respectively 3.2- and 29.5-fold less active than the BPP-BrachyNH(2)-induced ACE inhibitory activity. Molecular Dynamic and Molecular Mechanics Poisson-Boltzmann Surface Area simulations (MM-PBSA) demonstrated that the ACE/BBP-BrachyNH(2) complex showed lower binding and van der Wall energies than the ACE/des-Pro(8)-BPP-BrachyNH(2) complex, therefore having better stability. The removal of the N-terminal tryptophan increased the in silico predicted toxicological effects and cytotoxicity when compared with BPP-BrachyNH(2) or des-Pro(8)-BPP-BrachyNH(2). Otherwise, des-Pro(8)-BPP-BrachyNH(2) was 190-fold less cytotoxic than BPP-BrachyNH(2). Thus, the removal of C-terminal proline residue was able to markedly decrease both the BPP-BrachyNH(2)-induced ACE inhibitory and cytotoxic effects assessed by in vitro and in silico approaches. In conclusion, the aminoacid sequence of BPP-BrachyNH(2) is essential for its ACE inhibitory activity and associated with an acceptable toxicological profile. The perspective of the interactions of BPP-BrachyNH(2) with ACE found in the present study can be used for development of drugs with differential therapeutic profile than current ACE inhibitors. (C) 2017 Elsevier Masson SAS. All rights reserved. (AU)

• Processo FAPESP: 16/18023-5 - Estudos pré-clínicos da Epiisopiloturina e epiisopilosina e seus efeitos contra outros helmintos
• Beneficiário: Ana Carolina Mafud
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado