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1.
Molecules ; 27(15)2022 Jul 29.
Article in English | MEDLINE | ID: covidwho-1969391

ABSTRACT

Angiotensin receptor blockers (ARBs) used in the treatment of hypertension and potentially in SARS-CoV-2 infection exhibit inverse agonist effects at angiotensin AR1 receptors, suggesting the receptor may have evolved to accommodate naturally occurring angiotensin 'antipeptides'. Screening of the human genome has identified a peptide (EGVYVHPV) encoded by mRNA, complementary to that encoding ANG II itself, which is an inverse agonist. Thus, opposite strands of DNA encode peptides with opposite effects at AR1 receptors. Agonism and inverse agonism at AR1 receptors can be explained by a receptor 'switching' between an activated state invoking receptor dimerization/G protein coupling and an inverse agonist state mediated by an alternative/second messenger that is slow to reverse. Both receptor states appear to be driven by the formation of the ANG II charge-relay system involving TyrOH-His/imidazole-Carboxylate (analogous to serine proteases). In this system, tyrosinate species formed are essential for activating AT1 and AT2 receptors. ANGII is also known to bind to the zinc-coordinated metalloprotease angiotensin converting enzyme 2 (ACE2) used by the COVID-19 virus to enter cells. Here we report in silico results demonstrating the binding of a new class of anionic biphenyl-tetrazole sartans ('Bisartans') to the active site zinc atom of the endopeptidase Neprilysin (NEP) involved in regulating hypertension, by modulating humoral levels of beneficial vasoactive peptides in the RAS such as vasodilator angiotensin (1-7). In vivo and modeling evidence further suggest Bisartans can inhibit ANG II-induced pulmonary edema and may be useful in combatting SARS-CoV-2 infection by inhibiting ACE2-mediated viral entry to cells.


Subject(s)
COVID-19 Drug Treatment , Hypertension , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Humans , Hypertension/drug therapy , Neprilysin/metabolism , Peptidyl-Dipeptidase A/metabolism , Proto-Oncogene Mas , Receptors, Angiotensin/metabolism , Renin-Angiotensin System , SARS-CoV-2 , Zinc/pharmacology
2.
Curr Protein Pept Sci ; 23(5): 321-334, 2022.
Article in English | MEDLINE | ID: covidwho-1910825

ABSTRACT

Natriuretic peptide system (NPS) is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and natriuretic peptide precursor C (NPC), that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase (NEP), also known as neprilysin. Coronavirus disease 2019 (Covid-19) pandemic may lead to acute lung injury (ALI) and/or respiratory distress syndrome (ARDS). The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs and may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in managing Covid-19.


Subject(s)
COVID-19 Drug Treatment , Heart Failure , Respiratory Distress Syndrome , Aldosterone , Aminobutyrates , Anti-Inflammatory Agents , Atrial Natriuretic Factor/metabolism , Atrial Natriuretic Factor/therapeutic use , Biphenyl Compounds , Cathepsin G , Cytokines , Gastrin-Releasing Peptide/therapeutic use , Heart Failure/drug therapy , Humans , Natriuretic Peptide, Brain/metabolism , Natriuretic Peptide, Brain/therapeutic use , Natriuretic Peptides , Neprilysin/metabolism , Neprilysin/therapeutic use , Renin/therapeutic use , Tetrazoles/pharmacology , Tetrazoles/therapeutic use , Valsartan/therapeutic use
3.
Physiol Rep ; 9(5): e14796, 2021 03.
Article in English | MEDLINE | ID: covidwho-1120167

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a world-wide pandemic with overwhelming socioeconomic impact. Since inflammation is one of the major causes of COVID-19 complications, the associated molecular mechanisms have been the focus of many studies to better understand this disease and develop improved treatments for patients contracting SARS-CoV-2. Among these, strong emphasis has been placed on pro-inflammatory cytokines, associating severity of COVID-19 with so-called "cytokine storm." More recently, peptide bradykinin, its dysregulated signaling or "bradykinin storm," has emerged as a primary mechanism to explain COVID-19-related complications. Unfortunately, this important development may not fully capture the main molecular players that underlie the disease severity. To this end, in this focused review, several lines of evidence are provided to suggest that in addition to bradykinin, two closely related vasoactive peptides, substance P and neurotensin, are also likely to drive microvascular permeability and inflammation, and be responsible for development of COVID-19 pathology. Furthermore, based on published experimental observations, it is postulated that in addition to ACE and neprilysin, peptidase neurolysin (Nln) is also likely to contribute to accumulation of bradykinin, substance P and neurotensin, and progression of the disease. In conclusion, it is proposed that "vasoactive peptide storm" may underlie severity of COVID-19 and that simultaneous inhibition of all three peptidergic systems could be therapeutically more advantageous rather than modulation of any single mechanism alone.


Subject(s)
Bradykinin/metabolism , COVID-19/complications , Neprilysin/metabolism , Neurotensin/metabolism , Substance P/metabolism , Animals , COVID-19/metabolism , COVID-19/pathology , Cytokines/metabolism , Humans , Microvessels/metabolism , Microvessels/pathology , Post-Acute COVID-19 Syndrome
4.
Int J Mol Sci ; 21(22)2020 Nov 15.
Article in English | MEDLINE | ID: covidwho-927673

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Coronavirus Infections/drug therapy , Neprilysin/antagonists & inhibitors , Pneumonia, Viral/drug therapy , Aminobutyrates/administration & dosage , Aminobutyrates/therapeutic use , Angiotensin Receptor Antagonists/administration & dosage , Animals , Biphenyl Compounds , COVID-19 , Coronavirus Infections/metabolism , Drug Combinations , Humans , Neprilysin/metabolism , Pandemics , Pneumonia, Viral/metabolism , Tetrazoles/administration & dosage , Tetrazoles/therapeutic use , Valsartan/administration & dosage , Valsartan/therapeutic use
5.
Biochem Pharmacol ; 178: 114057, 2020 08.
Article in English | MEDLINE | ID: covidwho-378094

ABSTRACT

COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/prevention & control , Drug Repositioning/methods , Neprilysin/antagonists & inhibitors , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Signal Transduction/drug effects , Angiotensin I/pharmacology , Angiotensin I/therapeutic use , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/pharmacology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Drug Repositioning/statistics & numerical data , Drug Repositioning/trends , Humans , Neprilysin/metabolism , Peptide Fragments/pharmacology , Peptide Fragments/therapeutic use , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , SARS-CoV-2
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