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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Pernomian, Larissa [1] ; Gomes, Mayara S. [1] ; Tomich de Paula da Silva, Carlos H. [1] ; Rosa, Joaquin M. C. [1]
Total Authors: 4
[1] Univ Sao Paulo, Dept Biosci Appl Pharm, Fac Pharmaceut Sci Ribeirao Preto, POB 14040-903, Ribeirao Preto, SP - Brazil
Total Affiliations: 1
Document type: Review article
Source: Current Medicinal Chemistry; v. 24, n. 39, p. 4360-4367, 2017.
Web of Science Citations: 0

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)

FAPESP's process: 12/00640-7 - Study of the consequences of the inflammatory process induced by AT1 receptors during atherosclerosis on the ACE2 - angiotensin-(1-7) - Mas axis in mouse aorta and the involvement of Mas receptors in the vaso- and atheroprotective effects of losartan
Grantee:Larissa Pernomian
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 14/17740-0 - Planning, development and pharmacological evaluation of new aryl hydrocarbon receptors (AhR) antagonists that are candidates for atheroprotective drugs
Grantee:Larissa Pernomian
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 12/09019-3 - Consequences of dyslipidemia on the ACE - Ang II - AT1 and ACE2 - Ang-(1-7) - mas axes from the angiotensinergic system in aorta from young and adult LDLr knockout mice
Grantee:Ana Maria de Oliveira
Support type: Regular Research Grants