Published Online
on April 7, 2008

A more recent version of this article appeared on May 1, 2008

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Submitted on December 14, 2007
Revised on December 24, 2007

Structure-Based Identification of Small-Molecule Angiotensin-Converting Enzyme 2 Activators as Novel Antihypertensive Agents

José A. Hernández Prada; Anderson J. Ferreira; Michael J. Katovich; Vinayak Shenoy; Yanfei Qi; Robson A.S. Santos; Ronald K. Castellano; Andrew J. Lampkins; Vladimir Gubala; David A. Ostrov; and Mohan K. Raizada^*

From the McKnight Brain Institute (J.A.H.P., A.J.F., M.K.R.), and Departments of Physiology and Functional Genomics (J.A.H.P., A.J.F., M.K.R.), and Pathology, Immunology, and Laboratory Medicine (D.A.O.), College of Medicine, Department of Pharmacodynamics, College of Pharmacy (M.J.K., V.S., Y.Q.), and Department of Chemistry, College of Liberal Arts and Sciences (R.K.C., A.J.L., V.G.), University of Florida, Gainesville; and the Departments of Morphology (A.J.F.), and Physiology and Biophysics (R.A.S.S.), Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.

^* To whom correspondence should be addressed. E-mail: mraizada{at}phys.med.ufl.edu.

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.

Key words: structure-based drug design • angiotensin-converting enzyme 2 • virtual screening • molecular docking • cardiovascular disease • angiotensin (1-7)

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