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Planning, development and pharmacological evaluation of new aryl hydrocarbon receptors (AhR) antagonists that are candidates for atheroprotective drugs

Grant number: 14/17740-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): March 01, 2015
Effective date (End): May 31, 2016
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal researcher:Carlos Henrique Tomich de Paula da Silva
Grantee:Larissa Pernomian
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID


Cardiovascular diseases result from atherosclerotic lesions and account for 31% of the world mortality. A major risk factor for atherosclerosis is smoking, which enhances the atherogenic process upon the activation of aryl hydrocarbon receptors (AhR) evoked by cigarette smoke contaminants. These receptors belong to the bHLH/PAS protein superfamily and induce the expression of pro-atherogenic factors. Thus, there is a great interest in using AhR antagonist as atheroprotective drugs in smokers. However, the available AhR antagonist have several limitations (allosterism, partial agonist activity, non-selectivity, cytotoxicity, tendency to bioactivation), which avoids their evaluation in clinical studies. These limitations result from the lack of tridimensional information of the ligand binding domain (LBD) from AhR, which was mapped in the murine AhR as a small cavity inside the subdomain PAS-B, whose aromatic and hydrophobic character predicts that small chlorine-substituted planar aromatic chains are prototypes for nontoxic and resistant to biotransformation competitive pure selective antagonists. Thus, the aims from the present theoretical and experimental project are: (1) to plan and develop nontoxic and resistant to biotransformation competitive pure selective AhR antagonists by Computational Chemistry approaches, including molecular modifications proposals (virtual screening, bioisosterism) and the derivation of a common pharmacophore pattern to the existing active analogs by homology modeling; and (2) to evaluate the pharmacological properties from these compounds by biological assays. This project is linked to the CEPID/FAPESP 2013/08216-2.

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Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PERNOMIAN, LARISSA; GIMENES, LILIAN R.; GOMES, MAYARA S.; DO VALE, BRUNO N.; CARDOSO, CRISTINA R. B.; DE OLIVEIRA, ANA M.; MOREIRA, JOSIMAR D.. Endothelinergic Contractile Hyperreactivity in Rat Contralateral Carotid to Balloon Injury: Integrated Role for ETB Receptors and Superoxide Anion. BIOMED RESEARCH INTERNATIONAL, . (13/08216-2, 12/00640-7, 14/17740-0, 12/09019-3, 09/01005-0)
PERNOMIAN, LARISSA; PERNOMIAN, LAENA; GOMES, MAYARA S.; DA SILVA, CARLOS H. T. P.. Pharmacological significance of the interplay between angiotensin receptors: MAS receptors as putative final mediators of the effects elicited by angiotensin ATi receptors antagonists. European Journal of Pharmacology, v. 769, p. 143-146, . (13/08216-2, 12/00640-7, 11/11205-7, 14/17740-0)
PERNOMIAN, LARISSA; GOMES, MAYARA SANTOS; MOREIRA, JOSIMAR DORNELAS; TOMICH DE PAULA DA SILVA, CARLOS HENRIQUE; CAMPOS ROSA, JOAQUIN MARIA; DE BARROS CARDOSO, CRISTINA RIBEIRO. New Horizons on Molecular Pharmacology Applied to Drug Discovery: When Resonance Overcomes Radioligand Binding. CURRENT RADIOPHARMACEUTICALS, v. 10, n. 1, p. 16-20, . (12/00640-7, 14/17740-0, 12/09019-3)
PERNOMIAN, LARISSA; GOMES, MAYARA S.; PERNOMIAN, LAENA; MOREIRA, RAFAEL P.; CORREA, FERNANDO M. A.; DE OLIVEIRA, ANA M.. Vasoprotective effects of neurocompensatory response to balloon injury during diabetes involve the improvement of Mas signaling by TGF beta(1) activation. VASCULAR PHARMACOLOGY, v. 64, p. 36-48, . (09/01005-0, 11/11205-7, 14/17740-0, 13/08216-2, 12/00640-7)
PERNOMIAN, LARISSA; DA SILVA, CARLOS H. T. P.. Current basis for discovery and development of aryl hydrocarbon receptor antagonists for experimental and therapeutic use in atherosclerosis. European Journal of Pharmacology, v. 764, p. 118-123, . (13/08216-2, 14/17740-0)
PERNOMIAN, LARISSA; DO PRADO, ALEJANDRO F.; GOMES, MAYARA S.; PERNOMIAN, LAENA; DA SILVA, CARLOS H. T. P.; GERLACH, RAQUEL F.; DE OLIVEIRA, ANA M.. MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. European Journal of Pharmacology, v. 764, p. 173-188, . (13/08216-2, 12/00640-7, 14/17740-0, 12/09019-3)
MOREIRA, JOSIMAR D.; PERNOMIAN, LARISSA; GOMES, MAYARA S.; PERNOMIAN, LAENA; MOREIRA, RAFAEL P.; DO PRADO, ALEJANDRO F.; DA SILVA, CARLOS H. T. P.; DE OLIVEIRA, ANA M.. Acute restraint stress increases carotid reactivity in type-I diabetic rats by enhancing Nox4/NADPH oxidase functionality. European Journal of Pharmacology, v. 765, p. 503-516, . (13/08216-2, 11/11205-7, 14/17740-0)
PERNOMIAN, LARISSA; GOMES, MAYARA S.; TOMICH DE PAULA DA SILVA, CARLOS H.; ROSA, JOAQUIN M. C.. Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists. Current Medicinal Chemistry, v. 24, n. 39, p. 4360-4367, . (12/00640-7, 13/08216-2, 14/17740-0, 12/09019-3)

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