SARS-CoV-2 induces cardiomyocyte apoptosis and inflammation but can be ameliorated by ACE inhibitor Captopril.

Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with cardiovascular disease have higher severity of myocardial injury and poor outcomes. The underlying mechanism of myocardial injury caused by SARS-CoV-2 infection remains unclear. Using a non-transgenic mouse model infected with Beta variant (B.1.351), we found that the viral RNA could be detected in lungs and hearts of infected mice. Pathological analysis showed thinner ventricular wall, disorganized and ruptured myocardial fiber, mild inflammatory infiltration, and mild epicardia or interstitial fibrosis in hearts of infected mice. We also found that SARS-CoV-2 could infect cardiomyocytes and produce infectious progeny viruses in human pluripotent stem cell-derived cardiomyocyte-like cells (hPSC-CMs). SARS-CoV-2 infection caused apoptosis, reduction of mitochondrial integrity and quantity, and cessation of beating in hPSC-CMs. In order to dissect the mechanism of myocardial injury caused by SARS-CoV-2 infection, we employed transcriptome sequencing of hPSC-CMs at different time points after viral infection. Transcriptome analysis showed robust induction of inflammatory cytokines and chemokines, up-regulation of MHC class I molecules, activation of apoptosis signaling and cell cycle arresting. These may cause aggravate inflammation, immune cell infiltration, and cell death. Furthermore, we found that Captopril (hypotensive drugs targeting ACE) treatment could alleviate SARS-CoV-2 induced inflammatory response and apoptosis in cardiomyocytes via inactivating TNF signaling pathways, suggesting Captopril may be beneficial for reducing COVID-19 associated cardiomyopathy. These findings preliminarily explain the molecular mechanism of pathological cardiac injury caused by SARS-CoV-2 infection, providing new perspectives for the discovery of antiviral therapeutics.

Therapeutic approaches against coronaviruses acute respiratory syndrome.

Coronaviruses represent global health threat. In this century, they have already caused two epidemics and one serious pandemic. Although, at present, there are no approved drugs and therapies for the treatment and prevention of human coronaviruses, several agents, FDA-approved, and preclinical, have shown in vitro and/or in vivo antiviral activity. An in-depth analysis of the current situation leads to the identification of several potential drugs that could have an impact on the fight against coronaviruses infections. In this review, we discuss the virology of human coronaviruses highlighting the main biological targets and summarize the current state-of-the-art of possible therapeutic options to inhibit coronaviruses infections. We mostly focus on FDA-approved and preclinical drugs targeting viral conserved elements.

Regulation Mechanism for the Binding between the SARS-CoV-2 Spike Protein and Host Angiotensin-Converting Enzyme II.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is mainly mediated through the interaction between the spike protein (S-pro) of the virus and the host angiotensin-converting enzyme II (ACE2). The attachment of heparan sulfate (HS) to S-pro is necessary for its binding to ACE2. In this study, the binding process of the receptor-binding domain (RBD) of S-pro to ACE2 was explored by enhanced sampling simulations. The free-energy landscape was characterized to elucidate the binding mechanism of S-pro to ACE2 with and without HS fragment DP4. We found that the stability of the T470-F490 loop and the hydrophobic interactions contributed from F486/Y489 in the T470-F490 loop of S-pro are quite crucial for the binding, which is enhanced by the presence of DP4. Our study provides valuable insights for rational drug design to prevent the invasion of SARS-CoV-2.

Hypertension, a Moving Target in COVID-19: Current Views and Perspectives.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associates with a considerable high rate of mortality and represents currently the most important concern in global health. The risk of more severe clinical manifestation of COVID-19 is higher in males and steeply raised with age but also increased by the presence of chronic comorbidities. Among the latter, early reports suggested that arterial hypertension associates with higher susceptibility to SARS-CoV-2 infection, more severe course and increased COVID-19-related deaths. Furthermore, experimental studies suggested that key pathophysiological hypertension mechanisms, such as activation of the renin-angiotensin system (RAS), may play a role in COVID-19. In fact, ACE2 (angiotensin-converting-enzyme 2) is the pivotal receptor for SARS-CoV-2 to enter host cells and provides thus a link between COVID-19 and RAS. It was thus anticipated that drugs modulating the RAS including an upregulation of ACE2 may increase the risk for infection with SARS-CoV-2 and poorer outcomes in COVID-19. Since the use of RAS-blockers, ACE inhibitors or angiotensin receptor blockers, represents the backbone of recommended antihypertensive therapy and intense debate about their use in the COVID-19 pandemic has developed. Currently, a direct role of hypertension, independent of age and other comorbidities, as a risk factor for the SARS-COV-2 infection and COVID-19 outcome, particularly death, has not been established. Similarly, both current experimental and clinical studies do not support an unfavorable effect of RAS-blockers or other classes of first line blood pressure lowering drugs in COVID-19. Here, we review available data on the role of hypertension and its management on COVID-19. Conversely, some aspects as to how the COVID-19 affects hypertension management and impacts on future developments are also briefly discussed. COVID-19 has and continues to proof the critical importance of hypertension research to address questions that are important for global health.

Structure-aided ACEI-capped remdesivir-loaded novel PLGA nanoparticles: toward a computational simulation design for anti-SARS-CoV-2 therapy.

The sudden arrival of novel coronavirus disease 2019 (COVID-19) has stunned the world with its rapidly spreading virus. Remdesivir, a broad spectrum anti-viral drug, is now under in vitro and in vivo investigation as a potential agent against SARS-CoV-2. However, the results of this therapy were recently equivocal due to no significant benefit in the clinical trial. Herein, combination molecular docking with dissipative particle dynamics (DPD) simulations is used to theoretically design angiotensin-converting enzyme inhibitor (ACEI)-containing remdesivir-loaded PLGA nanoparticles (NPs) for anti-SARS-CoV-2 therapy. Based on the therapeutic and lung protective effect of ACEI, the classical lisinopril molecule covalently grafted onto PLGA (L-PLGA) has been used to encapsulate remdesivir. A binding model is used to confirm the interactions between lisinopril and ACE on the surface of cells, as well as remdesivir and its intracellular targeting protein (RNA-dependent RNA polymerase (RdRp)). Furthermore, DPD simulations are applied to study the nano-aggregation of drug-free L-PLGA, and remdesivir loaded in L-PLGA. The lisinopril molecules were directly demonstrated to be on the surface of L-PLGA NPs. Molecular docking proved that hydrogen bonding was decisive for the encapsulation of remdesivir. With an increase in concentration, remdesivir loaded L-PLGA formed spherical NPs, and then underwent precipitation. Similar to the above conditions, high remdesivir loading was also observed to cause precipitation formation. Thus, the optimized remdesivir NPs in our study give insights into a rational platform for formulation design against this global pandemic.

The interaction of RAAS inhibitors with COVID-19: Current progress, perspective and future.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently defined as the worst pandemic disease. SARS-CoV-2 infects human cells via the binding of its S protein to the receptor angiotensin-converting enzyme (ACE2). The use of ACEIs/ARBs (RAAS inhibitors) regulates the renin-angiotensin-aldosterone system (RAAS) and may increase ACE2 expression. Considering the large use of ACEIs/ARBs in hypertensive patients, some professional groups are concerned about whether the use of RAAS inhibitors affects the risk of SARS-CoV-2 infection or the risk of severe illness and mortality in COVID-19 patients. In this review, we summarize preclinical and clinical studies to investigate whether the use of ACEIs/ARBs increases ACE2 expression in animals or patients. We also analyzed whether the use of these drugs affects the risk of SARS-CoV-2 infection, severe illness or mortality based on recent studies. Finally, the review suggests that current evidence does not support the concerns.

ACE2, the Receptor that Enables Infection by SARS-CoV-2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators.

Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID-19). Thus, ACE2 is a potential target for drugs that disrupt the interaction of human cells with SARS-CoV-2 to abolish infection. There is also interest in drugs that inhibit or activate ACE2, that is, for cardiovascular disorders or colitis. Compounds binding at alternative sites could allosterically affect the interaction with the spike protein. Herein, we review biochemical, chemical biology, and structural information on ACE2, including the recent cryoEM structures of full-length ACE2. We conclude that ACE2 is very dynamic and that allosteric drugs could be developed to target ACE2. At the time of the 2020 pandemic, we suggest that available ACE2 inhibitors or activators in advanced development should be tested for their ability to allosterically displace the interaction between ACE2 and the spike protein.