Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists

Autor(es)

Pernomian, Larissa ^[1] ; Gomes, Mayara S. ^[1] ; Tomich de Paula da Silva, Carlos H. ^[1] ; Rosa, Joaquin M. C. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Biosci Appl Pharm, Fac Pharmaceut Sci Ribeirao Preto, POB 14040-903, Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo de Revisão
• Fonte: Current Medicinal Chemistry; v. 24, n. 39, p. 4360-4367, 2017.
• Citações Web of Science: 0

Resumo

Background: Protective effects of MAS activation have spurred clinical interests in developing MAS agonists. However, current bases that drive this process preclude that physiological concentrations of peptide MAS agonists induce an atypical signaling that does not reach the metabotropic efficacy of constitutive activation. Canonical activation of MAS-coupled G proteins is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological concentrations of chemically modified analogues. These pleiotropic differences are because of two overlapped binding domains: one non-metabotropic site that recognizes peptide agonists and one metabotropic domain that recognizes modified analogues. Objective: It is feasible that supraphysiological concentrations of peptide MAS agonists undergo to chemical modifications required for binding to metabotropic domain. Receptor oligomerization enhances pharmacological parameters coupled to metabotropic signaling. The formation of receptor-signalosome complex makes the transduction of agonists more adaptive. Considering the recent identification of MAS-signalosome, we aimed to postulate the reverse induced fit hypothesis in which MAS-signalosome would trigger chemical modifications required for agonists bind to MAS metabotropic domain. Methods: Here we cover rational perspectives for developing novel metabotropic MAS agonists in the view of the reverse induced-fit hypothesis. Results: Predicting a 3D model of MAS metabotropic domain may guide the screening of chemical modifications required for metabotropic efficacy. Pharmacophore-based virtual screening would select potential metabotropic MAS agonists from virtual libraries from human proteome. Conclusions: Rational perspectives that consider reverse induced fit hypothesis during MAS activation for developing metabotropic MAS agonists represents the best approach in providing MAS ligands with constitutive efficacy at physiological concentrations. (AU)

• Processo FAPESP: 12/00640-7 - Estudo das consequências do processo inflamatório induzido por receptores AT1 durante aterosclerose sobre o eixo ECA2 - angiotensina-(1-7) -Mas em aorta de camundongo e da participação de receptores Mas nos efeitos vaso- e ateroprotetores de losartan
• Beneficiário: Larissa Pernomian
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 14/17740-0 - Planejamento, desenvolvimento e avaliação farmacológica de novos antagonistas de receptores para hidrocarbonetos arila (AhR) candidatos a fármacos ateroprotetores
• Beneficiário: Larissa Pernomian
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/09019-3 - Consequências da dislipidemia sobre os eixos ECA - Ang II - AT1 e ECA2 - Ang-(1-7) - mas do sistema angiotensinérgico em aorta de camundongos LDLr knockout jovens e adultos
• Beneficiário: Ana Maria de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Regular