Molecular pharmacology of the mineralocorticoid receptor: Prospects for novel therapeutics

Kolkhof, Peter; Borden, Steffen A.

doi:10.1016/j.mce.2011.06.025

Cited by 131 publications

(103 citation statements)

References 78 publications

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“…Spironolactone was approved as a diuretic and natriuretic drug for the management of hypertension and primary aldosteronism and later on to treat heart failure (Menard, 2004). Spironolactone is a potent competitive MR antagonist but is poorly selective because it also inhibits the androgen and progesterone receptors, leading to side effects such as gynecomastia, impotence, and menstrual irregularities (Kolkhof and Borden, 2012). At high concentrations it may also interfere with the glucocorticoid receptor (GR) (Kolkhof and Borden, 2012).…”

Section: A Steroidal Compoundsmentioning

confidence: 99%

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

2015

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Section: A Steroidal Compoundsmentioning

confidence: 99%

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

2015

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“…22,23 The search for newer nonsteroidal MRAs that have superior selectivity and affinity for the MR began with the observation that some dihydropyridine calcium channel blockers compete with aldosterone for binding to the ligand binding domain of the MR and decrease aldosterone-mediated recruitment of transcriptional coactivators that are necessary for MR-directed DNA transcription. 22,24,25 Optimization of MRA activity of dihydropyridine compounds led to the development of BAY 94-8862 (finerenone), a nonsteroidal MRA that has greater selectivity than spironolactone for the MR over other steroid hormone receptors, greater affinity than eplerenone for the MR, and no effect on the L-type calcium channel 26,27 (Table). Finerenone was designed to have greater cardiac activity than the available steroidal MRAs to improve myocardial function without adversely affecting sodium-potassium homeostasis in the kidney.…”

Section: Mineralocorticoid Receptor Antagonistsmentioning

confidence: 99%

New Approaches in the Treatment of Hypertension

Oparil

Schmieder

2015

Circulation Research

243

137

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Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of the hypertensive population has uncontrolled blood pressure. The unmet need of controlling blood pressure in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. In this Compendium Review, we discuss new drugs and interventional treatments that are undergoing preclinical or clinical testing for hypertension treatment. New drug classes, eg, inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine β-hydroxylase, and the intestinal Na + /H + exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1–7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or preclinical development. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment resistant hypertension in some countries. Renal denervation is also being evaluated for treatment of various comorbidities, eg, chronic heart failure, cardiac arrhythmias and chronic renal failure. Novel interventional approaches in early development include carotid body ablation and arteriovenous fistula placement. Importantly, none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.

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“…SPR acts to block aldosterone activity by binding to the mineralocorticoid receptor and acting as a receptor antagonist (11). To ask whether SM inhibition by SPR was related to its mineralocorticoid blocking activity, we compared its effect on SM with that of eplerenone (EPR), a chemically similar congener also used clinically as an aldosterone antagonist (12). As shown in Fig.…”

Section: Antiviral Activity Of Spr Is Not Due To Mineralocorticoid Rementioning

confidence: 99%

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Verma

Thompson

Swaminathan

2016

Proc. Natl. Acad. Sci. U.S.A.

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Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses. . EBV infects the majority of humans worldwide and establishes a persistent, lifelong latent infection in memory B cells. Occasional reactivation from latency occurs, and EBV enters a lytic phase of replication, during which a tightly regulated series of lytic genes is expressed, culminating in lysis of the host cell and release of infectious viral progeny. All herpesviruses share these abilities to establish asymptomatic latent infection and reactivate intermittently.All herpesviruses also express a regulatory protein early in lytic replication that is essential for efficient gene expression and infectious virion production. The EBV member of this family, which includes herpes simplex virus ICP27, cytomegalovirus (CMV) UL69, and Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57, is known as SM (2). SM acts posttranscriptionally to enhance accumulation of many lytic EBV transcripts. SM activity is highly gene-specific and preferentially enhances expression of several late lytic transcripts, including those encoding the major viral capsid antigen (VCA) and gp350, which is required for infection of B lymphocytes (3-5). SM and its homologs in other herpesviruses may also enhance transcription and translation of specific viral genes (6).Currently, all available antiherpesvirus drugs target viral DNA polymerases and are usually highly effective, but toxicity and development of resistance limits their use (7). To discover potential novel therapeutic compounds, we applied a cell-based screening assay to identify compounds that would specifically target SM function (8). Using this assay, spironolactone (SPR), a drug in clinical use for over 50 y, was identified as inhibiting SM function and EBV virion production. SPR is an aldosterone antagonis...

show abstract

Molecular pharmacology of the mineralocorticoid receptor: Prospects for novel therapeutics

Cited by 131 publications

References 78 publications

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

New Approaches in the Treatment of Hypertension

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

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