Angiotensin-converting Enzyme Research Articles

Guideline-Directed Medical Therapy After Hospitalization for Acute Heart Failure: Insights From the CONNECT-HF.

Significant gap remains in the implementation of guideline-directed medical therapy (GDMT) in patients with heart failure after a hospitalization. We aimed to evaluate the use and titration of GDMT at discharge and over a 12-month period after hospital discharge and to identify factors associated with GDMT use and titration. The CONNECT-HF (Care Optimization Through Patient and Hospital Engagement Clinical Trial for Heart Failure) trial evaluated the effect of a hospital and postdischarge quality improvement intervention in participants with heart failure with reduced ejection fraction. In this secondary analysis, we examined use and titration to at least 50% of the target dose of GDMTs at hospital discharge and over time. Among 4646 participants (mean age 63 years, 34% women), GDMT use did not numerically improve from discharge to 12 months: beta blockers (84%-78%), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor-neprilysin inhibitors (73%-65%), mineralocorticoid receptor antagonists (39%-36%), and sodium-glucose cotransporter 2 inhibitors (1.5%-2.1%). Achieving ≥50% of the target dose also showed little change over 12 months: beta blockers (35%-32%), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor-neprilysin inhibitors (28%-25%). For all medications, use of GDMT at discharge was associated with the use and achieving ≥50% of the target dose at 12 months. Following a hospitalization for heart failure, GDMT use remained low and did not numerically improve over 12 months. Use of GDMT at discharge was significantly associated with the use of GDMT over time, highlighting the importance of initiating GDMT during hospitalization.

Quality of life, fatigue and markers in sarcoidosis: A section from Turkey.

Sarcoidosis can affect every organ with varying frequency based on ethnicity, gender and age. We aimed to evaluate the health-related quality of life (HRQoL) and fatigue levels of our sarcoidosis patients. However, our second aim is to determine whether patient or disease markers correlate with quality of life assessment questionnaires. Pulmonary sarcoidosis patients who were followed up in the chest diseases outpatient clinic of our hospital were included in this prospective study. In the follow-up of 2023, routine blood tests, angiotensin-converting enzyme (ACE), posteroanterior lung (thorax computed tomography in patients with parenchymal involvement) were requested from the patients. Participants were asked to fill out the short-form 36-item questionnaire (SF-36), fatigue assessment scale (FAS) and fatigue severity scale (FSS) under the control of the outpatient clinic. A total of 189 patients, 139 (73.5%) female and 50 (26.5%) male, diagnosed with Sarcoidosis were included. The mean age of our patients was 53.1±13.6. ACE (IU/L) 68.5±44.5. Of the patients we followed up for pulmonary sarcoidosis, 111 (58.7%) had single organ involvement and 78 (41.3%) had additional organ involvement. FAS; It was high in 103 (64.3%) patients and 29 (15.3%) were very tired. FSS value was 4.45±0.7 (3-5.88). All SF-36 parameters were lower than expected; MH and SF was minimally lower, PF, RP, BP, GH, RE and VT were significantly lower. SF-36 scores were found to be lower in the women and additional organ involvement participating. We found a significant decrease in HRQoL and an increase in fatigue scores of our patients. These changes were more pronounced in women participating in the study than in men. In addition, the involvement of additional organs with the lung negatively affected the quality of life.

Angiotensin-Converting Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) Use are Associated With Increased Readmission After Ileostomy Creation.

High output is a common cause for readmission after new ileostomy creation. The loss of sodium leads to compensatory activation of the renin-angiotensin-aldosterone system (RAAS). Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are first-line therapy for hypertension in the United States. We hypothesized that concurrent use of ACEI/ARB increases the risk of readmission following new ileostomy creation due to the loss of this compensatory mechanism. Patients undergoing ileostomy creation between 2009-2022 at an integrated managed health care system were included in this retrospective study. Primary outcomes were hospital readmission and ED visit within 30-days. Additional variables included ACEI/ARB use, ileostomy type, Charlson Comorbidity Index, additional antihypertensives at discharge (furosemide, hydrochlorothiazide, spironolactone, amlodipine, nifedipine, and diltiazem), and readmission diagnosis. Descriptive and advanced statistical analysis was completed with SPSS. Of 540 patients, 41.9% were readmitted or visited an ED within 30 days. There was no difference in readmission or ED visit based on age, gender, or ileostomy type. Patients discharged with ACEI/ARB (37.4% vs 25.5%, P = .005) and additional antihypertensives (37.2% vs 17.3%, P = .006) were at a higher risk for readmission. Inhibition of RAAS is associated with increased risk for hospital readmission. In patients with hypertension undergoing ileostomy creation, individualized care plans are needed with earlier antimotility agent use or intravenous rehydration plans.

Vasodilator drugs and heart-related outcomes in systemic sclerosis: an exploratory analysis

Background and aimsSystemic sclerosis (SSc) is an autoimmune connective disease characterised by excessive extracellular matrix deposition and widespread skin and internal organ fibrosis including various cardiac manifestations. Heart involvement is...

Generation of a SARS-CoV-2-susceptible mouse model using adenovirus vector expressing human angiotensin-converting enzyme 2 driven by an elongation factor 1α promoter with leftward orientation

IntroductionTo analyze the molecular pathogenesis of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a small animal model such as mice is needed: human angiotensin converting enzyme 2 (hACE2), the receptor of SARS-CoV-2, needs to be expressed in the respiratory tract of mice.MethodsWe conferred SARS-CoV-2 susceptibility in mice by using an adenoviral vector expressing hACE2 driven by an elongation factor 1α (EF1α) promoter with a leftward orientation.ResultsIn this model, severe pneumonia like human COVID-19 was observed in SARS-CoV-2-infected mice, which was confirmed by dramatic infiltration of inflammatory cells in the lung with efficient viral replication. An early circulating strain of SARS-CoV-2 caused the most severe weight loss when compared to SARS-CoV-2 variants such as Alpha, Beta and Gamma, although histopathological findings, viral replication, and cytokine expression characteristics were comparableDiscussionWe found that a distinct proteome of an early circulating strain infected lung characterized by elevated complement activation and blood coagulation, which were mild in other variants, can contribute to disease severity. Unraveling the specificity of early circulating SARS-CoV-2 strains is important in elucidating the origin of the pandemic.

QSAR Modeling of Substituted Benzimidazole Derivative as Angiotensin II-AT1 Receptor Antagonist: WHIM Descriptors

Selective inhibition of Angiotensin II (Ang II) is an important strategy for design of Ang II-AT1 receptor antagonist which is devoid of the common side effects of angiotensin converting enzyme inhibitors (ACEIs). QSAR study of 4, 5, 6, and 7 substituted benzimidazole analogs were performed using Dragon 2.1 (Milano Chemometrics) for antagonism of Ang II. The study was carried out on 33 compounds; mathematical models were obtained by means of the sequential multiple linear regression analysis (SMLR). QSAR analysis have produced good predictive models and give statistically significant correlations of selective Ang II antagonism with WHIM descriptors concerning size, symmetry, shape and distribution of molecules atom. The predictive ability of the resulting QSAR model was evaluated by cross validated correlation coefficient (q2 = 0.659). It was able to describe more than 68% of the variance in the experimental activity. This QSAR study helps in design and prediction of Ang II inhibitory activity of novel substituted benzimidazole Ang II-AT1 receptor antagonist.

Bioactive Peptides in Greek Goat Colostrum: Relevance to Human Metabolism

Colostrum is essential for the survival and development of newborn mammals. This primary source of nourishment during the first days of infant life is rich in functional components conductive to the enhancement of neonate immunity and growth. Compared with mature milk, a higher protein and peptide content is observed in colostrum, whilst it is low in fat and carbohydrates. The functional properties of colostrum are closely linked to the release of bioactive peptides during the gastrointestinal digestion of colostrum proteins. Our study aimed to comprehensively analyze the whey proteome of colostrum from indigenous Greek goats and to examine the influence of bioactive peptides released during digestion on human metabolism. Colostrum and mature milk samples from healthy ewes were subjected to nanoLC-MS/MS analysis, revealing differentially expressed proteins. These proteins were functionally characterized and subjected to in silico digestion. Using machine learning models, we classified the peptide functional groups, while molecular docking assessed the binding affinity of the proposed angiotensin-converting enzyme (ACE)- and dipeptidyl peptidase IV (DPPIV)-inhibitory peptides to their target molecules. A total of 898 proteins were identified in colostrum, 40 of which were overexpressed compared with mature milk. The enzymatic cleavage of upregulated proteins by key gastrointestinal tract proteases and the downstream analysis of peptide sequences identified 117 peptides predicted (with >80% confidence) to impact metabolism, primarily through modulation of the renin–angiotensin system, insulin secretion, and redox pathways. This work advances our understanding of dietary bioactive peptides and their relevance to human metabolism, highlighting the potential health benefits of colostrum consumption.

Altered plasma levels of the SARS-CoV-2-related proteins ACE2 and TMPRSS2 in patients with Crohn’s disease

The SARS-CoV-2 coronavirus infects cells through the cellular receptor angiotensin-converting enzyme 2 (ACE2), and the protease TMPRSS2 for the priming of viral spike protein. Thus, changes in these key proteins due to chronic conditions can increase risk for SARS-CoV2 infection; but significance of changes may differ is these changes correspond to full-length species or proteolytic fragments. Here, we determined that full-length ACE2 decreased in the plasma of uninfected Crohn’s disease (CD) patients before treatment onset compared to controls. TMPRSS2 is mostly presented in plasma as full-length species and as an active peptidase fragment, but also as a prodomain fragment, which is the unique species remarkably decreased in plasma from CD patients. Patients treated with the anti-TNFα adalimumab showed recovery in ACE2 levels, while those treated with infliximab, or with the anti-IL-12/23 ustekinumab, still displayed a decrease in full-length species, as well as in cleaved fragments. Patients treated with azathioprine displayed similar ACE2 levels to that of controls, except a decrease in one of the ACE2 fragments. Uniquely, patients treated with azathioprine or with ustekinumab showed partial recovery in the reduction of the TMPRSS2-prodomain fragment characterized in treatment-naïve patients. Our data suggest that CD and common therapies are not related to increased susceptibility for SARS-CoV-2.

Comparison of Gene Polymorphisms of ACE1 and ACE2 and the Level of Total ACE Activity in the Blood of Afghans and Iranians with COVID-19 and Its Relationship with Disease Severity.

Field evidence indicates differences in the rate and severity of COVID-19 infection among Afghans and Iranians, potentially influenced by individual genomic variances. Therefore, investigating the potential causes of these disparities holds significant clinical importance. This study aims to explore and compare variations in the genes encoding angiotensin-converting enzyme 1 (ACE1) and angiotensin-converting enzyme 2 (ACE2), along with total ACE activity levels in the blood of Afghans and Iranians with COVID-19, to assess any potential correlation with disease severity. In this case-control study, 124 Afghans and 124 Iranians with COVID-19 residing in Rafsanjan city, Iran, were examined. Blood samples were collected from all subjects, and serum was isolated for measuring total ACE activity using the kinetic method. DNA extraction was performed using the salting-out method, and gene polymorphisms of ACE1 and ACE2 were determined through polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism techniques. The DD genotype and D allele, as well as the GG genotype and G allele, were more prevalent among individuals with severe COVID-19 cases compared with those with mild symptoms, indicating an increased risk of severe infection. Although the Iranian group exhibited higher levels of these genetic components, along with longer hospital stays, intensive care unit admissions, and mortality rates than the Afghan group, the differences were not statistically significant. Furthermore, individuals with the DD genotype displayed double the total ACE activity levels compared with those with the II genotype, with the ID genotype falling in between. The presence of the DD genotype and D allele, as well as the GG genotype and G allele, likely serves as a significant risk factor for COVID-19 susceptibility, potentially heightening the risk of severe infection among Iranians compared with Afghans.

Investigation of the Interaction Between Angiotensin-Converting Enzyme (ACE) and ACE-Inhibitory Tripeptide from Casein

Angiotensin-converting enzyme (ACE) inhibitory peptides exhibit antihypertensive effects by inhibiting ACE activity, and the study of the interaction between ACEs and inhibitory peptides is important for exploring new therapeutic strategies. In this study, the ACE-inhibitory peptide isolated from casein hydrolysate with the amino acid sequence Leu–Leu–Tyr (LLY) exhibited high ACE-inhibitory activity and stability, which holds significant implications for biochemistry and pharmaceutical applications. Furthermore, systematic investigations were conducted on the interaction between ACE and LLY through various approaches. The Lineweaver–Burk plot indicated the non-competitive inhibition pattern of LLY, suggesting that it binds to the enzyme at the non-active site, and the results were further validated by a molecular docking study. Additionally, multispectral experiments and atomic force microscopy were conducted to further elucidate the underlying mechanism of peptide activity. The findings indicated that LLY could induce a conformational change in ACE, thereby inhibiting its activity. This study contributes to a deeper understanding of the mechanism of action of ACE-inhibitory peptides and bears important significance for drug development in hypertension.

Cell‐Sensing Analogue Nanopore for Rapid Detection of Protein‐Related Targets

AbstractNanopores offer significant advantages in biosensing. Conventional nanopore sensors require probe modification within the pore, and there are two major obstacles: inhomogeneity of probe modification within the pore, and distortion of the detection signal due to the uncontrollable dynamics of the target within the pore. Here, we constructed a cell‐sensing analogue nanopore (CeSa‐nanopore), by coating the outer surface of the nanopore with cell membrane. The inhomogeneity of probe modification and the uncontrollable kinetics of target‐probe binding were also addressed. Specific cells are selected to prepare CeSa‐nanopore, for example, cells with high expression of angiotensin‐converting enzyme 2 (ACE2) are used to achieve the detection of SARS‐CoV‐2. When SARS‐CoV‐2 binds to CeSa‐nanopore the surface potential changes, causing a change in the ionic current, thus enabling its detection with a detection rate of 100 %. In addition, the detection of different proteins, such as follicle‐stimulating hormone (FSH), can be achieved by changing the cell membrane coating. The identification of cancer cells in ascites can also be achieved by utilizing homologous targeting between cancer cells. Importantly, the use of CeSa‐nanopores for the detection of these targets eliminates the need for pre‐processing and significantly reduces detection time.

ACE2, From the Kidney to SARS-CoV-2: Donald Seldin Award Lecture 2023.

ACE2 (angiotensin-converting enzyme 2) is a monocarboxypeptidase that cleaves Ang II (angiotensin II) among other substrates. ACE2 is present in the cell membrane of many organs, most abundantly in epithelial cells of kidney proximal tubules and the small intestine, and also exists in soluble forms in plasma and body fluids. Membrane-bound ACE2 exerts a renoprotective action by metabolizing Ang II and therefore attenuating the undesirable actions of excess Ang II. Therefore, soluble ACE2, by downregulating this peptide, may exert a therapeutic action. Our laboratory has designed ACE2 truncates that pass the glomerular filtration barrier to target the kidney renin-angiotensin system directly and, therefore, compensate for loss of kidney membrane-bound ACE2. Membrane-bound ACE2 is also the essential receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble ACE2 proteins have been studied as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 and prevent cell entry of SARS-CoV-2 altogether. We bioengineered a soluble ACE2 protein, termed ACE2 618-DDC-ABD, with increased binding affinity for SARS-CoV-2 and prolonged duration of action, which, when administered intranasally, provides near-complete protection from lethality in k18hACE2 mice infected with different SARS-CoV-2 variants. The main advantage of soluble ACE2 proteins for the neutralization of SARS-CoV-2 is their immediate onset of action and universality for current and future emerging SARS-CoV-2 variants. It is notable that ACE2 is critically involved in 2 dissimilar functions: as a receptor for cell entry of many coronaviruses and as an enzyme in the metabolism of Ang II, and yet in both cases, it is a therapeutic target.

Effects of digoxin in inhibiting ACE2 and SARS-CoV-2 binding for attenuating COVID-19 in human adipocytes

BACKGROUND Angiotensin-converting enzyme 2 (ACE2) has a role in SARS-CoV-2 incidence, and digoxin is a competitive inhibitor of SARS-CoV-2-ACE2 binding. This study aimed to investigate the effects of digoxin on SARS-CoV-2-ACE2 binding, proinflammatory cytokines, and prothrombotic factors in adipocytes of patients with COVID-19. METHODS This in vitro study used adipocyte cultures, which were divided into negative control, positive control (SARS-CoV-2 S1 spike protein only), SARS-CoV-2 S1 spike protein with digoxin, and SARS-CoV-2 S1 spike protein with human recombinant soluble ACE2 (hrsACE2). Data were analyzed using one-way ANOVA and Pearson correlation. RESULTS SARS-CoV-2 significantly elevated ACE2 and increased interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), tissue factor (TF), and plasminogen activator inhibitor-1 (PAI-1) compared to the negative control group (p<0.001). No SARS-CoV-2-ACE2 binding was detected in SARS-CoV-2 with digoxin and hrsACE2 groups, compared to the positive control group (0 ng/ml versus 0 ng/ml versus 36.33 [1.58] ng/ml, p<0.001). Digoxin significantly decreased IL-6 (48.94 [1.80] ng/ml versus 90.93 [4.29] ng/ml; p<0.001), TNF-α (87.65 [6.88] ng/ml versus 307.95 [57.34] ng/ml; p<0.001), TF (5.33 [0.32] ng/ml versus 6.85 [0.22] ng/ml; p<0.001), and PAI-1 levels (2.92 [0.168] ng/ml versus 4.86 [0.11] ng/ml; p<0.001), compared to positive control group. ACE2 positively correlated with IL-6 (p = 0.004, r = 0.763) and TF (p = 0.004, r = 0.768) but was not correlated with IL-1β, TNF-α, and PAI-1 levels. CONCLUSIONS This study promoted digoxin therapy to prevent cytokine storm and thromboembolism by decreasing IL-6, TNF-α, TF, and PAI-1 in adipocyte cultured models at an early stage of COVID-19.

Antihypertensive Effect of Perla and Esmeralda Barley (Hordeum vulgare L.) Sprouts in an Induction Model with L-NAME In Vivo

Background: Hypertension is one of the leading causes of premature death worldwide. Despite advances in conventional treatments, there remains a significant need for more effective and natural alternatives to control hypertension. In this context, sprouted barley extracts have emerged as a potential therapeutic option. This study presents the evaluation of the bioactive properties of extracts from two varieties of barley germinated for different periods (3, 5, and 7 days), focusing on their potential to regulate blood pressure mechanisms. Objectives/Methods: The main objective was to assess the effects of these extracts on blood pressure regulation in N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME)-induced hypertensive rats. Renal (creatinine, urea, uric acid, and total protein) and endothelial (NOx levels) function, angiotensin-converting enzyme (ACE) I and II activity, and histopathological effects on heart and kidney tissues were evaluated. Results: In particular, Esmeralda barley extract demonstrated 83% inhibition of ACE activity in vitro. Furthermore, the combined administration of sprouted barley extract (SBE) and captopril significantly reduced blood pressure and ACE I and II activity by 22%, 81%, and 76%, respectively, after 3, 5, and 7 days of germination. The treatment also led to reductions in protein, creatinine, uric acid, and urea levels by 3%, 38%, 42%, and 48%, respectively, along with a 66% increase in plasma NO concentrations. Conclusions: This study highlights the bioactive properties of barley extracts with different germination times, emphasizing their potential health benefits as a more effective alternative to conventional antihypertensive therapies.

Genetic polymorphisms influencing antihypertensive drug responses.

Hypertension is a major contributor to cardiovascular disease and its associated morbidity and mortality. The low efficacy observed with some anti-hypertensive therapies has been attributed partly to inter-individual genetic variability. This paper reviews the major findings regarding these genetic variabilities that modulate responses to anti-hypertensive therapies such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, calcium channel blockers (CCBs) and β-adrenoceptor blockers. The importance of studying these genetic polymorphisms stems from the goal to optimise anti-hypertensive therapy for each individual patient, aiming for the highest efficacy and lowest risk of adverse effects. It is important to recognise that environmental and epigenetic factors can contribute to the observed variations in drug responses. Owing to the multigenic and multifactorial nature of drug responses, further research is crucial for translating these findings into clinical practice and the establishment of reliable recommendations.

Clinical characteristics and in-hospital event rate of chronic obstructive pulmonary disease patients with concurrent acute myocardial infarction

This study was to investigate the clinical features of chronic obstructive pulmonary disease (COPD) patients with concurrent acute myocardial infarction (AMI) and analyze the occurrence of in-hospital adverse events. Patients with AMI who were admitted to Beijing Chaoyang Hospital from January 2019 to August 2023 were retrospectively collected. All patients were divided into COPD with concurrent AMI group and simple AMI group according to whether they were with concurrent COPD. All patients received interventional treatment for AMI. The clinical features and the occurrence of in-hospital adverse events were compared between the two groups. A total of 183 AMI patients aged (65.6±13.6) years were enrolled, including 142 males (77.6%). There were 94 patients (51.4%) in simple AMI group and 89 patients (48.6%) in COPD with concurrent AMI group, respectively. Patients in COPD with concurrent AMI group were older, had higher Killip grade, rate of smoking and previous percutaneous coronary intervention history, creatinine and B-type natriuretic peptide levels, and lower albumin, hemoglobin, low-density lipoprotein cholesterol, white blood cell count and cardiac troponin I than those of simple AMI group (all P<0.05). There were no significant differences in echocardiographic parameters between the two groups (all P>0.05). The proportion of β-blockers, angiotensin-converting enzyme inhibitors/angiotensin-blockers used in COPD with concurrent AMI group was lower (P<0.05). Patients in COPD with concurrent AMI group had longer length of hospital stay than those in simple AMI group (P=0.028). The incidence of primary endpoint events in COPD with concurrent AMI group was higher than that in simple AMI group (27.0% vs 18.0%, P=0.002). The current study indicates that COPD patients with concurrent AMI have longer length of hospital stay and higher incidence of in-hospital events, which are worthy of significant attention in clinical practice.

Impedimetric Sensor for SARS-CoV-2 Spike Protein Detection: Performance Assessment with an ACE2 Peptide-Mimic/Graphite Interface

The COVID-19 pandemic has prompted the need for the development of new biosensors for SARS-CoV-2 detection. Particularly, systems with qualities such as sensitivity, fast detection, appropriate to large-scale analysis, and applicable in situ, avoiding using specific materials or personnel to undergo the test, are highly desirable. In this regard, developing an electrochemical biosensor based on peptides derived from the angiotensin-converting enzyme receptor 2 (ACE2) is a possible answer. To this end, an impedimetric detector was developed based on a graphite electrode surface modified with an ACE2 peptide-mimic. This sensor enables accurate quantification of recombinant 2019-nCoV spike RBD protein (used as a model analyte) within a linear detection range of 0.167–0.994 ng mL−1, providing a reliable method for detecting SARS-CoV-2. The observed sensitivity was further demonstrated by molecular dynamics that established the high affinity and specificity of the peptide to the protein. Unlike other impedimetric sensors, the herein presented system can detect impedance in a single frequency, allowing a measure as fast as 3 min to complete the analysis and achieving a detection limit of 45.08 pg mL−1. Thus, the proposed peptide-based electrochemical biosensor offers fast results with adequate sensitivity, opening a path to new developments concerning other viruses of interest.

Coronil effectively inhibits the interaction of clinically relevant Omicron mutants of SARS-CoV-2 Spike Proteins with human ACE2 receptor

BackgroundAccumulating evidence suggests that the receptor binding domain (RBD) of the SARS-CoV-2 Omicron variant has several times more binding affinity to the human angiotensin-converting enzyme 2 (ACE2) receptor compared to the RBD of the original covid-19 strain. This increased binding affinity of the Omicron variant is responsible for its increased internalization and infectivity. PurposeIn the present study, the impact of Coronil, a tri-herbal formulation of extracts from Withania somnifera, Tinospora cordifolia and Ocimum sanctum on the binding properties of Omicron SARS-CoV-2 variant spike proteins (S proteins) was investigated. MethodsChemical composition of Coronil was determined by the Prominence-XR UHPLC system. The ELISA-based ACE2 binding inhibition assay was performed to delineate the effect of Coronil on the interaction between human ACE2 receptor and different Omicron variant S-proteins such as BA.4/BA5, XBB, BA.2.75.2, BA4.6/BF.7, BA.2.75.2, BQ.1.1 and a recently found spike protein variant JN.1 which is thought to emerge from BA.2.86. ResultsCoronil showed a dose-dependent inhibitory effect on the interactions between ACE2 and receptor binding domains (RBD) of all variants of S-proteins evaluated in this study including the recently emerged, highly transmissible variant spike protein JN.1. Although, Coronil significantly reduced the binding percentage in almost all the variant spike proteins, the maximum inhibition was achieved against BA.4/BA.5 where it inhibited the S protein – ACE2 interaction even at a low concentration of 3 µg/ml (16.6 %). This binding inhibition was further increased to 60.3 and 84.6 % at 100 and 300 µg/ml respectively. ConclusionThis capability of Coronil to inhibit the binding of S-protein variants with ACE2 receptor may interfere with viral binding and internalization resulting in reduced infectivity of these Omicron spike protein variants. Overall, our data underscores the potential of Coronil in combating the various newly emerged Omicron spike protein variants. These findings may provide a basis for further studies of Coronil for its clinical effectiveness against these Omicron variants.

BMY 7378, a selective α1D-adrenoceptor antagonist, is a new angiotensin converting enzyme inhibitor: In silico, in vitro and in vivo approach

BMY 7378 is a multitarget drug primarily known for its selective antagonism of α1D-adrenoceptors (α1D-AR), exhibiting both hypotensive effects and the ability to prevent or reverse angiotensin II-induced vascular hypertrophy. Notably, BMY 7378 contains a phenylpiperazine moiety, a structural feature associated with angiotensin-converting enzyme (ACE) inhibition. This study aimed to investigate ACE inhibition as a potential pharmacological mechanism of BMY 7378. Using an in silico approach we predicted BMY 7378 interactions with the ACE active site, followed by in vitro activity assays. Additionally, ACE protein expression in the heart was analyzed following four weeks of BMY 7378 treatment in 7–8-month-old spontaneously hypertensive rats (SHR). All assays were benchmarked against captopril, a standard ACE inhibitor. In silico results showed that BMY 7378 binds to the ACE active site, though with reduced interaction with Zn701 (73.7 % compared to captopril), likely due to the pKa of its amino group. The inhibitory concentration 50 (IC50) for BMY 7378 was 136 μM, lower than other reported phenylpiperazine derivatives. Furthermore, BMY 7378 significantly increased ACE expression in the hearts of SHR, with an increase of 8.5-fold compared to captopril. In conclusion, BMY 7378 exhibits dual activity as an α1D-AR antagonist and an ACE inhibitor, making it a promising pharmacological tool for investigating and potentially treating hypertension and its associated cardiovascular complications.

Potential blood pressure regulatory effect of low molecular weight α-chymotrypsin extract and its peptides from Stichopus japonicus: Peptide-ACE interaction study via in silico molecular docking

Hypertension is a significant risk factor for cardiovascular disease and heart damage. Stichopus japonicus (S. japonicus) is a red sea cucumber with antioxidant and anti-hypertensive activities. However, its anti-hypertensive mechanism remains unclear. In this study, we evaluated the inhibitory effects of angiotensin-converting enzyme (ACE) of α-chymotrypsin-assisted hydrolysate of S. japonicus (α-chy) and its ultrafiltrate fractions (>10 kDa [α-chy-I], 5–10 kDa [α-chy-II], and <5 kDa [α-chy-III]). Low molecular α-chy-III exerted excellent ACE inhibitory and anti-hypertensive activities in spontaneously hypertensive rats (SHR). Moreover, α-chy-III significantly reduced the systolic and diastolic blood pressure by modulating the serum angiotensin and ACE levels. Histological analysis revealed that α-chy-III markedly protected the aorta, heart, and kidney tissues of SHR from hypertension-induced tissue damage.Taken together, our findings highlight the potential of α-chy-III as a functional food ingredient for the treatment of hypertension and its comorbidities.