Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin—Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme

Sharma, Urvashi; Cozier, Gyles E.; Sturrock, Edward D.; Acharya, K. Ravi

doi:10.1021/acs.jmedchem.0c00441

Cited by 16 publications

(17 citation statements)

References 45 publications

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“…3,45 In the absence of a hydrophobic sidechain at this P 1 ′ position, as is the case for omapatrilat, an alternative binding pose is observed in NEP, where the P 1 group binds to S 1 ′ subsite (Figure S1). 43,46,47 Based on previous studies and the structure of LisW, three dipeptides containing an N-terminal nitrogen capped with 1carboxy-3-phenylpropyl were synthesized to probe the requirements of the ACE and NEP prime subsites for dual cACE/ NEP inhibition (Figure 2). The terminal amine of the butyl sidechain was removed in LisW analogues AD011 and AD012, improving NEP inhibitory activity.…”

Section: ■ Resultsmentioning

confidence: 99%

Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition

et al. 2022

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Selective inhibition of the angiotensin-converting enzyme C-domain (cACE) and neprilysin (NEP), leaving the ACE N-domain (nACE) free to degrade bradykinin and other peptides, has the potential to provide the potent antihypertensive and cardioprotective benefits observed for nonselective dual ACE/NEP inhibitors, such as omapatrilat, without the increased risk of adverse effects. We have synthesized three 1-carboxy-3-phenylpropyl dipeptide inhibitors with nanomolar potency based on the previously reported C-domain selective ACE inhibitor lisinopriltryptophan (LisW) to probe the structural requirements for potent dual cACE/NEP inhibition. Here we report the synthesis, enzyme kinetic data, and high-resolution crystal structures of these inhibitors bound to nACE and cACE, providing valuable insight into the factors driving potency and selectivity. Overall, these results highlight the importance of the interplay between the S 1 ′ and S 2 ′ subsites for ACE domain selectivity, providing guidance for future chemistry efforts toward the development of dual cACE/NEP inhibitors.

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Section: ■ Resultsmentioning

confidence: 99%

Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition

et al. 2022

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“…Long-term ACEi usage also results in undesirable BK build-up which causes vascular injury and increased endothelial permeability or angioedema. Joint NEP and ACE inhibitors, such as omapatrilat, have been designed to block ACE-dependent Ang II production and decrease NEP-dependent degradation of vasodilators [ 93 ]. However, these can have more serious side effects than ACE inhibitors alone when targeting both ACE domains, due to BK accumulation [ 93 ].…”

Section: Arb and Acei: Effects On Immune Abilitiesmentioning

confidence: 99%

“…Joint NEP and ACE inhibitors, such as omapatrilat, have been designed to block ACE-dependent Ang II production and decrease NEP-dependent degradation of vasodilators [ 93 ]. However, these can have more serious side effects than ACE inhibitors alone when targeting both ACE domains, due to BK accumulation [ 93 ]. Combination therapies alongside domain-selective ACE inhibitors have been explored to reduce these side effects and maintain BP control.…”

Section: Arb and Acei: Effects On Immune Abilitiesmentioning

confidence: 99%

“…These findings are clinically important for the ACEi lisinopril-tryptophan and NEP inhibitor sacubitril, where hypertension was normalised without the loss of endothelial function and vascular permeability [ 94 ]. Furthermore, joint NEP and ACE inhibitors could be beneficial if designed to favour ACE C-domain over N-domain binding [ 93 ]. In contrast, sacubitril ARB therapy had no significant improvement in hypertensive mice, whereas NEP and ACE inhibition using omapatrilat was able to reduce BP but did not prevent BK build-up in mice, preventing stabilisation of Ang II and BP levels.…”

Section: Arb and Acei: Effects On Immune Abilitiesmentioning

confidence: 99%

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Exploring the Impact of ACE Inhibition in Immunity and Disease

Oosthuizen

Sturrock

2022

J Renin Angiotensin Aldosterone Syst

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Angiotensin-converting enzyme (ACE) is a zinc-dependent dipeptidyl carboxypeptidase and is crucial in the renin-angiotensin-aldosterone system (RAAS) but also implicated in immune regulation. Intrinsic ACE has been detected in several immune cell populations, including macrophages and neutrophils, where its overexpression results in enhanced bactericidal and antitumour responses, independent of angiotensin II. With roles in antigen presentation and inflammation, the impact of ACE inhibitors must be explored to understand how ACE inhibition may impact our ability to clear infections or malignancy, particularly in the wake of the coronavirus (SARS-CoV2) pandemic and as antibiotic resistance grows. Patients using ACE inhibitors may be more at risk of postsurgical complications as ACE inhibition in human neutrophils results in decreased ROS and phagocytosis whilst angiotensin receptor blockers (ARBs) have no effect. In contrast, ACE is also elevated in certain autoimmune diseases such as rheumatoid arthritis and lupus, and its inhibition benefits patient outcome where inflammatory immune cells are overactive. Although the ACE autoimmune landscape is changing, some studies have conflicting results and require further input. This review seeks to highlight the need for further research covering ACE inhibitor therapeutics and their potential role in improving autoimmune conditions, cancer, or how they may contribute to immunocompromise during infection and neurodegenerative diseases. Understanding ACE inhibition in immune cells is a developing field that will alter how ACE inhibitors are designed in future and aid in developing therapeutic interventions.

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“…Altogether, the findings illustrate that BK is highly unstable and may contribute to the acquired AE associated with ACE inhibitors if, for some reason, important generation of kinins is triggered. The development of double peptidase inhibitors for ACE and neutral endopeptidase (neprilysin) is still being contemplated as an anti-hypertensive after the failure of omapatrilat, which caused relatively frequent AE attacks [ 38 ]. The possible importance of the rapid clearance of BK for patients with HAE is the protection from the continuous production of BK, as judged from HK consumption and kallikrein activity (see below).…”

Section: Probing Immunoreactive Bk Degradation In Vitromentioning

confidence: 99%

In Vitro Modeling of Bradykinin-Mediated Angioedema States

et al. 2020

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Kinins (peptides related to bradykinin, BK) are formed from circulating substrates, the kininogens, by the action of two proteases, the kallikreins. The only clinical application of a BK receptor ligand, the B2 receptor antagonist icatibant, is the treatment of the rare hereditary angioedema (HAE) caused by the deficiency of C1-esterase inhibitor (C1-INH). Less common forms of HAE (genetic variants of factor XII, plasminogen, kininogen) are presumably mediated by increased BK formation. Acquired forms of BK-mediated angioedema, such as that associated with angiotensin-I converting enzyme (ACE) inhibition, are also known. Antibody-based analytical techniques are briefly reviewed, and support that kinins are extremely short-lived, prominently cleared by ACE. Despite evidence of continuous activation of the kallikrein–kinin system in HAE, patients are not symptomatic most of the time and their blood or plasma obtained during remission does not generate excessive immunoreactive BK (iBK), suggesting effective homeostatic mechanisms. HAE-C1-INH and HAE-FXII plasmas are both hyperresponsive to fibrinolysis activation. On another hand, we suggested a role for the alternate tissue kallikrein–kinin system in patients with a plasminogen mutation. The role of the BK B1 receptor is still uncertain in angioedema states. iBK profiles under in vitro stimulation provide fresh insight into the physiopathology of angioedema.

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Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin—Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme

Cited by 16 publications

References 45 publications

Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition

Probing the Requirements for Dual Angiotensin-Converting Enzyme C-Domain Selective/Neprilysin Inhibition

Exploring the Impact of ACE Inhibition in Immunity and Disease

In Vitro Modeling of Bradykinin-Mediated Angioedema States

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