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Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents

Hernandez Prada, J.A., Ferreira, A.J., Katovich, M.J., Shenoy, V., Qi, Y., Santos, R.A.S., Castellano, R.K., Lampkins, A.J., Gubala, V., Ostrov, D.A., and others. (2008) Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension, 51 (5). pp. 1312-1317. ISSN 0194-911X. (doi:10.1161/HYPERTENSIONAHA.107.108944) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided)

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Abstract

Angiotensin-converting enzyme 2 (ACE2) is a key renin-angiotensin system enzyme involved in balancing the adverse effects of angiotensin II on the cardiovascular system, and its overexpression by gene transfer is beneficial in cardiovascular disease. Therefore, our objectives were 2-fold: to identify compounds that enhance ACE2 activity using a novel conformation-based rational drug discovery strategy and to evaluate whether such compounds reverse hypertension-induced pathophysiologies. We used a unique virtual screening approach. In vitro assays revealed 2 compounds (a xanthenone and resorcinolnaphthalein) that enhanced ACE2 activity in a dose-dependent manner. Acute in vivo administration of the xanthenone resulted in a dose-dependent transient and robust decrease in blood pressure (at 10 mg/kg, spontaneously hypertensive rats decreased 71±9 mm Hg and Wistar-Kyoto rats decreased 21±8 mm Hg; P<0.05). Chronic infusion of the xanthenone (120 μg/day) resulted in a modest decrease in the spontaneously hypertensive rat blood pressure (17 mm Hg; 2-way ANOVA; P<0.05), whereas it had no effect in Wistar-Kyoto rats. Strikingly, the decrease in blood pressure was also associated with improvements in cardiac function and reversal of myocardial, perivascular, and renal fibrosis in the spontaneously hypertensive rats. We conclude that structure-based screening can help identify compounds that activate ACE2, decrease blood pressure, and reverse tissue remodeling. Administration of ACE2 activators may be a valid strategy for antihypertensive therapy. © 2008 American Heart Association, Inc.

Item Type: Article
DOI/Identification number: 10.1161/HYPERTENSIONAHA.107.108944
Additional information: Unmapped bibliographic data: LA - English [Field not mapped to EPrints] J2 - Hypertension [Field not mapped to EPrints] C2 - 18391097 [Field not mapped to EPrints] AD - McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, United States [Field not mapped to EPrints] AD - Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, United States [Field not mapped to EPrints] AD - Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States [Field not mapped to EPrints] AD - Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States [Field not mapped to EPrints] AD - Department of Chemistry, College of Liberal Arts and Sciences, University of Florida, Gainesville, FL, United States [Field not mapped to EPrints] AD - Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil [Field not mapped to EPrints] AD - Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil [Field not mapped to EPrints] AD - Department of Physiology and Functional Genomics, PO Box 100274, Gainesville, FL 32610, United States [Field not mapped to EPrints] DB - Scopus [Field not mapped to EPrints]
Uncontrolled keywords: Angiotensin (1-7), Angiotensin-converting enzyme 2, Cardiovascular disease, Molecular docking, Structure-based drug design, Virtual screening, angiotensin converting enzyme 2, antihypertensive agent, enzyme activator, resorcinolnaphthalein, unclassified drug, xanthenone, animal experiment, animal model, antihypertensive activity, article, blood pressure, controlled study, dose response, drug effect, drug identification, enzyme activity, heart function, heart muscle fibrosis, heart rate, hypertension, in vitro study, in vivo study, kidney fibrosis, male, nonhuman, priority journal, rat, vascular fibrosis, Animals, Antihypertensive Agents, Blood Pressure, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Design, Enzyme Activators, Heart, Hypertension, Male, Peptidyl-Dipeptidase A, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Resorcinols, Structure-Activity Relationship, Xanthenes
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Vladimir Gubala
Date Deposited: 14 Dec 2017 21:29 UTC
Last Modified: 29 May 2019 13:41 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/45247 (The current URI for this page, for reference purposes)
Gubala, V.: https://orcid.org/0000-0001-6301-3632
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