COVID-19 and Cardiovascular Disease.

Coronavirus disease 2019 (COVID-19) is a global pandemic affecting 185 countries and >3 000 000 patients worldwide as of April 28, 2020. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2, which invades cells through the angiotensin-converting enzyme 2 receptor. Among patients with COVID-19, there is a high prevalence of cardiovascular disease, and >7% of patients experience myocardial injury from the infection (22% of critically ill patients). Although angiotensin-converting enzyme 2 serves as the portal for infection, the role of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers requires further investigation. COVID-19 poses a challenge for heart transplantation, affecting donor selection, immunosuppression, and posttransplant management. There are a number of promising therapies under active investigation to treat and prevent COVID-19.

Endosomes, receptors, and viruses.

Mechanisms of infection are deciphered at the host-pathogen interface.

The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies.

The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.

[Renin-Angiotensin-System (RAS) and COVID-19 - On The Prescription of RAS Blockers]. / Renin-Angiotensin-System (RAS) und COVID-19 ­ Zur Verordnung von RAS-Blockern.

Twenty years ago, an enzyme homologous to the previously known angiotensin-converting enzyme (ACE) was identified, and subsequently named ACE2. In the renin-angiotensin system (RAS), ACE2 has counter-regulatory functions against the classical effector peptide angiotensin II, for example in blood pressure regulation and cardiovascular remodeling. However, ACE2 provides an initially unexpected interesting link between virology and cardiovascular medicine. That is, ACE2 represents the binding receptor for the cellular uptake of SARS-CoV and SARS-CoV-2 viruses. Thus, ACE2 is relevant for COVID-19. In this context, it was suspected that therapy with RAS blockers might promote transmission and complications of COVID-19 by upregulation of ACE2 expression. The aim of this short review is, to describe the link between the RAS, particularly ACE2, and COVID-19. Based on our analysis and evaluation of the available findings, we justify our conclusion: important drugs such as ACE inhibitors and angiotensin receptor blockers should continue to be prescribed according to guidelines to stable patients in the context of the COVID-19 pandemic.

Thiol-based chemical probes exhibit antiviral activity against SARS-CoV-2 via allosteric disulfide disruption in the spike glycoprotein.

The development of small-molecules targeting different components of SARS-CoV-2 is a key strategy to complement antibody-based treatments and vaccination campaigns in managing the COVID-19 pandemic. Here, we show that two thiol-based chemical probes that act as reducing agents, P2119 and P2165, inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, the angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine profiling link the antiviral activity to the reduction of key disulfides, specifically by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol-reducing moiety pointed directly toward Cys432. These collective findings establish the vulnerability of human coronaviruses to thiol-based chemical probes and lay the groundwork for developing compounds of this class, as a strategy to inhibit the SARS-CoV-2 infection by shifting the spike glycoprotein redox scaffold.

DNA aptamers masking angiotensin converting enzyme 2 as an innovative way to treat SARS-CoV-2 pandemic.

All the different coronavirus SARS-CoV-2 variants isolated so far share the same mechanism of infection mediated by the interaction of their spike (S) glycoprotein with specific residues on their cellular receptor: the angiotensin converting enzyme 2 (ACE2). Therefore, the steric hindrance on this cellular receptor created by a bulk macromolecule may represent an effective strategy for the prevention of the viral spreading and the onset of severe forms of Corona Virus disease 19 (COVID-19). Here, we applied a systematic evolution of ligands by exponential enrichment (SELEX) procedure to identify two single strand DNA molecules (aptamers) binding specifically to the region surrounding the K353, the key residue in human ACE2 interacting with the N501 amino acid of the SARS-CoV-2 S. 3D docking in silico experiments and biochemical assays demonstrated that these aptamers bind to this region, efficiently prevent the SARS-CoV-2 S/human ACE2 interaction and the viral infection in the nanomolar range, regardless of the viral variant, thus suggesting the possible clinical development of these aptamers as SARS-CoV-2 infection inhibitors. Our approach brings a significant innovation to the therapeutic paradigm of the SARS-CoV-2 pandemic by protecting the target cell instead of focusing on the virus; this is particularly attractive in light of the increasing number of viral mutants that may potentially escape the currently developed immune-mediated neutralization strategies.

Switching Sides: How Endogenous Retroviruses Protect Us from Viral Infections.

Long disregarded as junk DNA or genomic dark matter, endogenous retroviruses (ERVs) have turned out to represent important components of the antiviral immune response. These remnants of once-infectious retroviruses not only regulate cellular immune activation, but may even directly target invading viral pathogens. In this Gem, we summarize mechanisms by which retroviral fossils protect us from viral infections. One focus will be on recent advances in the role of ERVs as regulators of antiviral gene expression.

Investigating interactions between chloroquine/hydroxychloroquine and their single enantiomers and angiotensin-converting enzyme 2 by a cell membrane chromatography method.

Chloroquine and hydroxychloroquine have been studied since the early clinical treatment of SARS-CoV-2 outbreak. Considering these two chiral drugs are currently in use as the racemate, high-expression angiotensin-converting enzyme 2 cell membrane chromatography was established for investigating the differences of two paired enantiomers binding to angiotensin-converting enzyme 2 receptor. Molecular docking assay and detection of SARS-CoV-2 spike pseudotyped virus entry into angiotensin-converting enzyme 2-HEK293T cells were also conducted for further investigation. Results showed that each single enantiomer could bind well to angiotensin-converting enzyme 2, but there were differences between the paired enantiomers and corresponding racemate in frontal analysis. R-Chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine. Moreover, each single enantiomer was proved effective compared with the control group; compared with S-chloroquine or the racemate, R-chloroquine showed better inhibitory effects at the same concentration. As for hydroxychloroquine, R-hydroxychloroquine showed better inhibitory effects than S-hydroxychloroquine, but it slightly worse than the racemate. In conclusion, R-chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability and inhibitory effects compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine (racemate), while the effect of preventing SARS-CoV-2 pseudovirus from entering cells was weaker than R-hydroxychloroquine/hydroxychloroquine (racemate).

Molecular screening of glycyrrhizin-based inhibitors against ACE2 host receptor of SARS-CoV-2.

The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process. Interfering with this event represents an attractive avenue for the development of therapeutics and vaccine development. Here, a hybrid approach of ligand- and structure-based virtual screening techniques were employed to disclose similar analogues of a reported antiviral phytochemical, glycyrrhizin, targeting the blockade of ACE2 interaction with the SARS-CoV-2 Spike. A ligand-based similarity search using a stringent cut-off revealed 40 FDA-approved compounds in DrugBank. These filtered hits were screened against ACE2 using a blind docking approach to determine the natural binding tendency of the compounds with ACE2. Three compounds, deslanoside, digitoxin, and digoxin, were reported to show strong binding with ACE2. These compounds bind at the H1-H2 binding pocket, in a manner similar to that of glycyrrhizin which was used as a control. To achieve consistency in the docking results, docking calculations were performed via two sets of docking software that predicted binding energy as ACE2-Deslanoside (AutoDock, -10.3 kcal/mol and DockThor, -9.53 kcal/mol), ACE2-Digitoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.84 kcal/mol), and ACE2-Digoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.81 kcal/mol). The docking results were validated by running molecular simulations in aqueous solution that demonstrated the stability of ACE2 with no major conformational changes in the ligand original binding mode (~ 2 Å average RMSD). Binding interactions remained quite stable with an increased potential for getting stronger as the simulation proceeded. MMGB/PBSA binding free energies were also estimated and these supported the high stability of the complexes compared to the control (~ -50 kcal/mol net MMGB/PBSA binding energy versus ~ -30 kcal/mol). Collectively, the data demonstrated that the compounds shortlisted in this study might be subjected to experimental evaluation to uncover their real blockade capacity of SARS-CoV-2 host ACE2 receptor.

Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants.

Resistance represents a major challenge for antibody-based therapy for COVID-191-4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern-B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)-and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.

Review of studies of severe acute respiratory syndrome related coronavirus-2 pathogenesis in human organoid models.

Severe acute respiratory syndrome related coronavirus-2 (SARS-CoV-2) is the cause of Covid-19 which was classified as a global pandemic in March 2020. The increasing global health and economic burden of SARS-CoV-2 has necessitated urgent investigations into the pathogenesis of disease and development of therapeutic and vaccination regimens. Human trials of vaccine and antiviral candidates have been undertaken, but basic pathogenetic studies are still required to inform these trials. Gaps in understanding of cellular infection by, and immunity to, SARS-CoV-2 mean additional models are required to assist in improved design of these therapeutics. Human organoids are three-dimensional models that contain multiple cell types and mimic human organs in ex vivo culture conditions. The SARS-CoV-2 virus has been implicated in causing not only respiratory injury but also injury to other organs such as the brain, liver and kidneys. Consequently, a variety of different organoid models have been employed to investigate the pathogenic mechanisms of disease due to SARS-CoV-2. Data on these models have not been systematically assembled. In this review, we highlight key findings from studies that have utilised different human organoid types to investigate the expression of SARS-CoV-2 receptors, permissiveness, immune response, dysregulation of cellular functions, and potential antiviral therapeutics.

Tetracycline as an inhibitor to the SARS-CoV-2.

The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an extant threat against public health on a global scale. Cell infection begins when the spike protein of SARS-CoV-2 binds with the human cell receptor, angiotensin-converting enzyme 2 (ACE2). Here, we address the role of tetracycline as an inhibitor for the receptor-binding domain (RBD) of the spike protein. Targeted molecular investigation show that tetracycline binds more favorably to the RBD (-9.40 kcal/mol) compared to doxycycline (-8.08 kcal/mol), chloroquine (-6.31 kcal/mol), or gentamicin (-4.83 kcal/mol) while inhibiting attachment to ACE2 to a greater degree (binding efficiency of 2.98 kcal/(mol nm2 ) for tetracycline-RBD, 5.16 kcal/(mol nm2 ) for doxycycline-RBD, 5.59 kcal/(mol nm2 ) for chloroquine-RBD, and 7.02 kcal/(mol nm2 ) for gentamicin-RBD. Stronger inhibition by tetracycline is verified with nonequilibrium PMF calculations, for which the tetracycline-RBD complex exhibits the lowest free energy profile along the dissociation pathway from ACE2. Tetracycline binds to tyrosine and glycine residues on the viral contact interface that are known to modulate molecular recognition and bonding affinity. These RBD residues also engage in significant hydrogen bonding with the human receptor ACE2. The ability to preclude cell infection complements the anti-inflammatory and cytokine suppressing capability of tetracycline; this may reduce the duration of ICU stays and mechanical ventilation induced by the coronavirus SARS-CoV-2.

Nanoluciferase complementation-based bioreporter reveals the importance of N-linked glycosylation of SARS-CoV-2 S for viral entry.

The ongoing COVID-19 pandemic has highlighted the immediate need for the development of antiviral therapeutics targeting different stages of the SARS-CoV-2 life cycle. We developed a bioluminescence-based bioreporter to interrogate the interaction between the SARS-CoV-2 viral spike (S) protein and its host entry receptor, angiotensin-converting enzyme 2 (ACE2). The bioreporter assay is based on a nanoluciferase complementation reporter, composed of two subunits, large BiT and small BiT, fused to the S receptor-binding domain (RBD) of the SARS-CoV-2 S protein and ACE2 ectodomain, respectively. Using this bioreporter, we uncovered critical host and viral determinants of the interaction, including a role for glycosylation of asparagine residues within the RBD in mediating successful viral entry. We also demonstrate the importance of N-linked glycosylation to the RBD's antigenicity and immunogenicity. Our study demonstrates the versatility of our bioreporter in mapping key residues mediating viral entry as well as screening inhibitors of the ACE2-RBD interaction. Our findings point toward targeting RBD glycosylation for therapeutic and vaccine strategies against SARS-CoV-2.

The Ineluctable Role of ACE-2 Receptors in SARS COV-2 Infection and Drug Repurposing as a Plausible SARS COV-2 Therapy: A Concise Treatise.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent for the COVID-19 infectious disease that spreads via the respiratory route and has reached a drastic level of a global pandemic. Symptoms of COVID-19 may vary from mild (fever, dry cough, shortness of breath) to severe pneumonia-like respiratory symptoms as exacerbation of disease occurs. Unlike SARS-CoV, the SARSCoV- 2 has a higher binding affinity to ACE-2 receptors, which signifies its higher transmission rate from person to person. Even though ACE-2 is significant in the reninangiotensin- aldosterone system (RAAS) regulation that exhibits protection to various organs, it plays a significant role in COVID-19 disease pathogenesis. Viral interferences with the ACE-2 peptidase activity are found in SARS-CoV-2 infected patients leading to pro-inflammatory responses, hypertension and multi-organ damage. Angiotensinconverting enzyme-2 is constrained to a variety of organ systems, but surface ACE-2 receptors on lung epithelia are largely affected, which lead to pathological alterations in lung histology which may progress to respiratory failure. The viral tropism mainly occurs by the attachment to the angiotensin-converting enzymes-2 receptors in the host cell; thus drugs targeting ACE-2 expressions may arise as the future therapeutic strategy to combat COVID-19 infections. The innovative approach of repurposing drugs has shown temporary effectiveness to curb the rising pandemic. This article mainly focuses on the prominence of ACE-2 receptors which are expressed during the COVID infections and the repurposing strategy of available drug therapies.

An Updated Review on Betacoronavirus Viral Entry Inhibitors: Learning from Past Discoveries to Advance COVID-19 Drug Discovery.

Even after one year of its first outbreak reported in China, the coronavirus disease 2019 (COVID-19) pandemic is still sweeping the World, causing serious infections and claiming more fatalities. COVID-19 is caused by the novel coronavirus SARS-CoV-2, which belongs to the genus Betacoronavirus (ß-CoVs), which is of greatest clinical importance since it contains many other viruses that cause respiratory disease in humans, including OC43, HKU1, SARS-CoV, and MERS. The spike (S) glycoprotein of ß-CoVs is a key virulence factor in determining disease pathogenesis and host tropism, and it also mediates virus binding to the host's receptors to allow viral entry into host cells, i.e., the first step in virus lifecycle. Viral entry inhibitors are considered promising putative drugs for COVID-19. Herein, we mined the biomedical literature for viral entry inhibitors of other coronaviruses, with special emphasis on ß-CoVs entry inhibitors. We also outlined the structural features of SARS-CoV-2 S protein and how it differs from other ß-CoVs to better understand the structural determinants of S protein binding to its human receptor (ACE2). This review highlighted several promising viral entry inhibitors as potential treatments for COVID-19.

Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy.

The human serine protease serine 2 TMPRSS2 is involved in the priming of proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and represents a possible target for COVID-19 therapy. The TMPRSS2 gene may be co-expressed with SARS-CoV-2 cell receptor genes angiotensin-converting enzyme 2 (ACE2) and Basigin (BSG), but only TMPRSS2 demonstrates tissue-specific expression in alveolar cells according to single-cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 gene based on genome-wide data from 76 human populations demonstrates that a functionally significant missense mutation in exon 6/7 in the TMPRSS2 gene is found in many human populations at relatively high frequencies, with region-specific distribution patterns. The frequency of the missense mutation encoded by rs12329760, which has previously been found to be associated with prostate cancer, ranged between 10% and 63% and was significantly higher in populations of Asian origin compared with European populations. In addition to single-nucleotide polymorphisms, two copy number variants were detected in the TMPRSS2 gene. A number of microRNAs have been predicted to regulate TMPRSS2 and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well-studied drugs can downregulate the expression of TMPRSS2 in human cells, including acetaminophen (paracetamol) and curcumin. Thus, the interactions of TMPRSS2 with SARS-CoV-2, together with its structural variability, gene-gene interactions, expression regulation profiles, and pharmacogenomic properties, characterize this gene as a potential target for COVID-19 therapy.

ACE2 as a Potential Target for Management of Novel Coronavirus (nCoV- 2019).

A novel coronavirus termed nCoV-2019 that caused an epidemic of acute respiratory syndrome in humans was first detected in Wuhan, China, in December 2019. nCoV-2019 resulted in thousands of cases of lethal disease all around the world. Unfortunately, there is no specific treatment yet, so a better understanding of the pathobiology of the disease can be helpful. The renin-angiotensin system and its products have several important physiological actions. On the other hand, this system is involved in the pathogenesis of various diseases. In this context, this review article will briefly discuss insights for understanding the role of the angiotensin-converting enzyme 2 (ACE2) receptor as a potentially attractive target for the nCoV-2019-induced acute respiratory syndrome.

Phytopharmaceuticals mediated Furin and TMPRSS2 receptor blocking: can it be a potential therapeutic option for Covid-19?

BACKGROUND: Currently, novel coronavirus disease (Covid-19) outbreak creates global panic across the continents, as people from almost all countries and territories have been affected by this highly contagious viral disease. The scenario is deteriorating due to lack of proper & specific target-oriented pharmacologically safe prophylactic agents or drugs, and or any effective vaccine. drug development is urgently required to back in the normalcy in the community and to combat this pandemic. PURPOSE: Thus, we have proposed two novel drug targets, Furin and TMPRSS2, as Covid-19 treatment strategy. We have highlighted this target-oriented novel drug delivery strategy, based on their pathophysiological implication on SARS-CoV-2 infection, as evident from earlier SARS-CoV-1, MERS, and influenza virus infection via host cell entry, priming, fusion, and endocytosis. STUDY DESIGN &  METHODS: An earlier study suggested that Furin and TMPRSS2 knockout mice had reduced level of viral load and a lower degree of organ damage such as the lung. The present study thus highlights the promise of some selected novel and potential anti-viral Phytopharmaceutical that bind to Furin and TMPRSS2 as target. RESULT: Few of them had shown promising anti-viral response in both preclinical and clinical study with acceptable therapeutic safety-index. CONCLUSION: Hence, this strategy may limit life-threatening Covid-19 infection and its mortality rate through nano-suspension based intra-nasal or oral nebulizer spray, to treat mild to moderate SARS-COV-2 infection when Furin and TMPRSS2 receptor may initiate to express and activate for processing the virus to cause cellular infection by replication within the host cell and blocking of host-viral interaction.