Angiotensin-(1-7) with Thioether Bridge: An Angiotensin-Converting Enzyme-Resistant, Potent Angiotensin-(1-7) Analog

Kluskens, Leon; Nelemans, S. A.; Rink, Rick; Vries, Louwe de; Meter-Arkema, Anita; Wang, Yong; Walther, Thomas; Kuipers, Anneke; Moll, Gert N.; Haas, M

doi:10.1124/jpet.108.146431

Cited by 133 publications

(120 citation statements)

References 37 publications

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“…This receptor can be blocked by D-Pro 7 -Ang-(1-7), and its identification solves some earlier discrepant findings with the Mas antagonist A-779. [18][19][20] This observation is in line with our finding that Ang-(1-7) can be processed to alamandine in the isolated rat heart. Furthermore, we demonstrated that human ACE2 forms alamandine from angiotensin A, reinforcing the central role of this enzyme in the processing of angiotensin peptides.…”

Section: Ace2supporting

confidence: 81%

Discovery and Characterization of Alamandine

Lautner¹,

Villela²,

Fraga‐Silva³

et al. 2013

Circulation Research

336

266

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n the past few years, novel components of the renin-angiotensin system (RAS) have been described, including the prorenin/ renin receptor, 1 angiotensin-converting enzyme-2 (ACE2), 2,3 and Mas.4 ACE2 and Mas are now considered to be part of a novel axis of the RAS, the ACE2/angiotensin 1 to 7 [Ang-(1-7)]/Mas axis, 4-11 which counteracts most of the action of the classical Rationale: The renin-angiotensin system (RAS) is a key regulator of the cardiovascular system, electrolyte, and water balance. Here, we report identification and characterization of alamandine, a new heptapeptide generated by catalytic action of angiotensin-converting enzyme-2 angiotensin A or directly from angiotensin-(1-7).Objective: To characterize a novel component of the RAS, alamandine. Methods and Results:Using mass spectrometry we observed that alamandine circulates in human blood and can be formed from angiotensin-(1-7) in the heart. Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Key Words: angiotensin II ■ antihypertensive treatment ■ cardiovascular system ■ hypertension ■ renin-angiotensin system ■ vasoactive peptides ■ vascular reactivity Original received February 7, 2013; revision received February 22, 2013; accepted February 27, 2013. In January 2013, the average time from submission to first decision for all original research papers submitted to Circulation Research was 12.2 days.Brief UltraRapid Communications are designed to be a format for manuscripts that are of outstanding interest to the readership, report definitive observations, but have a relatively narrow scope. Less comprehensive than Regular Articles but still scientifically rigorous, BURCs present seminal findings that have the potential to open up new avenues of research. A decision on BURCs is rendered within 7 days of submission.From the

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Section: Ace2supporting

confidence: 81%

Discovery and Characterization of Alamandine

Lautner¹,

Villela²,

Fraga‐Silva³

et al. 2013

Circulation Research

336

266

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“…Subsequently, we have demonstrated that not only NisB but also the nisin cyclase NisC has broad substrate specificity (39). We recently demonstrated the enhanced stability, activity, and bioavailability (19) and oral and pulmonary delivery (5) of thioether-bridged angiotensin- (1-7).…”

Section: Discussionmentioning

confidence: 99%

Requirements of the Engineered Leader Peptide of Nisin for Inducing Modification, Export, and Cleavage

Plat¹,

Kluskens²,

Kuipers³

et al. 2011

Appl Environ Microbiol

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164

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Nisin A is a pentacyclic peptide antibiotic produced by Lactococcus lactis. The leader peptide of prenisin keeps nisin inactive and has a role in inducing NisB-and NisC-catalyzed modifications of the propeptide and NisT-mediated export. The highly specific NisP cleaves off the leader peptide from fully modified and exported prenisin. We present here a detailed mutagenesis analysis of the nisin leader peptide. For alternative cleavage, we successfully introduced a putative NisP autocleavage site and sites for thrombin, enterokinase, Glu-C, and factor Xa in the C-terminal part of the leader peptide. Replacing residue F-18 with Trp or Thr strongly reduced production. On the other hand, D-19A, F-18H, F-18M, L-16D, L-16K, and L-16A enhanced production. Substitutions within and outside the FNLD box enhanced or reduced the transport efficiency. None of the above substitutions nor even an internal 6His tag from positions ؊13 to ؊8 had any effect on the capacity of the leader peptide to induce NisB and NisC modifications. Therefore, these data demonstrate a large mutational freedom. However, simultaneous replacement of the FNLD amino acids by four alanines strongly reduced export and even led to a complete loss of the capacity to induce modifications. Reducing the leader peptide to MSTKDFNLDLR led to 3-or 4-fold dehydration. Taken together, the FNLD box is crucial for inducing posttranslational modifications.

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“…59,60 These studies were limited in scope, and native Ang(1-7) has not been developed further because of its abbreviated half-life in vivo. A cyclic Ang(1-7) analog containing a thioether bridge that makes it resistant to enzymatic digestion and a hydroxypropyl-β-cyclodextrin incorporated Ang(1-7) formulation (HP-β-CD/Ang1-7) have been synthesized and shown to be cardioprotective in animal models of myocardial infarction and insulin resistance/type 2 diabetes [61][62][63] (Table). As an alternative to Ang(1-7), nonpeptide agonists of the Mas receptor, for example, the imidazole compound AVE0991, 64 and novel G-protein-coupled receptor activating peptides, for example, CGEN-856S that have high specificity for the Mas receptor, 65 have been shown to lower BP and protect the vasculature and kidneys in animal models of hypertension and CVD (Table).…”

Section: Activators Of the Angiotensin-converting Enzyme2/angiotensinmentioning

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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Angiotensin-(1-7) with Thioether Bridge: An Angiotensin-Converting Enzyme-Resistant, Potent Angiotensin-(1-7) Analog

Abstract: The

Cited by 133 publications

References 37 publications

Discovery and Characterization of Alamandine

Discovery and Characterization of Alamandine

Requirements of the Engineered Leader Peptide of Nisin for Inducing Modification, Export, and Cleavage

New Approaches in the Treatment of Hypertension

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