3D Lung Tissue Models for Studies on SARS-CoV-2 Pathophysiology and Therapeutics

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has provoked more than six million deaths worldwide and continues to pose a major threat to global health. Enormous efforts have been made by researchers around the world to elucidate COVID-19 pathophysiology, design efficacious therapy and develop new vaccines to control the pandemic. To this end, experimental models are essential. While animal models and conventional cell cultures have been widely utilized during these research endeavors, they often do not adequately reflect the human responses to SARS-CoV-2 infection. Therefore, models that emulate with high fidelity the SARS-CoV-2 infection in human organs are needed for discovering new antiviral drugs and vaccines against COVID-19. Three-dimensional (3D) cell cultures, such as lung organoids and bioengineered organs-on-chips, are emerging as crucial tools for research on respiratory diseases. The lung airway, small airway and alveolus organ chips have been successfully used for studies on lung response to infection by various pathogens, including corona and influenza A viruses. In this review, we provide an overview of these new tools and their use in studies on COVID-19 pathogenesis and drug testing. We also discuss the limitations of the existing models and indicate some improvements for their use in research against COVID-19 as well as future emerging epidemics.     

Autophagy,Unfolded Protein Response,and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

The COVID-19 pandemic is caused by the 2019–nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.     

Perspective of the Relationship between the Susceptibility to Initial SARS-CoV-2 Infectivity and Optimal Nasal Conditioning of Inhaled Air

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as with the influenza virus, has been shown to spread more rapidly during winter. Severe coronavirus disease 2019 (COVID-19), which can follow SARS-CoV-2 infection, disproportionately affects older persons and males as well as people living in temperate zone countries with a tropical ancestry. Recent evidence on the importance of adequately warming and humidifying (conditioning) inhaled air in the nasal cavity for reducing SARS-CoV-2 infectivity in the upper respiratory tract (URT) is discussed, with particular reference to: (i) the relevance of air-borne SARS-CoV-2 transmission, (ii) the nasal epithelium as the initial site of SARS-CoV-2 infection, (iii) the roles of type 1 and 3 interferons for preventing viral infection of URT epithelial cells, (iv) weaker innate immune responses to respiratory viral infections in URT epithelial cells at suboptimal temperature and humidity, and (v) early innate immune responses in the URT for limiting and eliminating SARS-CoV-2 infections. The available data are consistent with optimal nasal air conditioning reducing SARS-CoV-2 infectivity of the URT and, as a consequence, severe COVID-19. Further studies on SARS-CoV-2 infection rates and viral loads in the nasal cavity and nasopharynx in relation to inhaled air temperature, humidity, age, gender, and genetic background are needed in this context. Face masks used for reducing air-borne virus transmission can also promote better nasal air conditioning in cold weather. Masks can, thereby, minimise SARS-CoV-2 infectivity and are particularly relevant for protecting more vulnerable persons from severe COVID-19.     

Correlation between Type I Interferon Associated Factors and COVID-19 Severity

Antiviral type I interferons (IFN) produced in the early phase of viral infections effectively inhibit viral replication, prevent virus-mediated tissue damages and promote innate and adaptive immune responses that are all essential to the successful elimination of viruses. As professional type I IFN producing cells, plasmacytoid dendritic cells (pDC) have the ability to rapidly produce waste amounts of type I IFNs. Therefore, their low frequency, dysfunction or decreased capacity to produce type I IFNs might increase the risk of severe viral infections. In accordance with that, declined pDC numbers and delayed or inadequate type I IFN responses could be observed in patients with severe coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as compared to individuals with mild or no symptoms. Thus, besides chronic diseases, all those conditions, which negatively affect the antiviral IFN responses lengthen the list of risk factors for severe COVID-19. In the current review, we would like to briefly discuss the role and dysregulation of pDC/type I IFN axis in COVID-19, and introduce those type I IFN-dependent factors, which account for an increased risk of COVID-19 severity and thus are responsible for the different magnitude of individual immune responses to SARS-CoV-2.     

Understanding Viral Infection Mechanisms and Patient Symptoms for the Development of COVID-19 Therapeutics

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has become a worldwide pandemic. Symptoms range from mild fever to cough, fatigue, severe pneumonia, acute respiratory distress syndrome (ARDS), and organ failure, with a mortality rate of 2.2%. However, there are no licensed drugs or definitive treatment strategies for patients with severe COVID-19. Only antiviral or anti-inflammatory drugs are used as symptomatic treatments based on clinician experience. Basic medical researchers are also trying to develop COVID-19 therapeutics. However, there is limited systematic information about the pathogenesis of COVID-19 symptoms that cause tissue damage or death and the mechanisms by which the virus infects and replicates in cells. Here, we introduce recent knowledge of time course changes in viral titers, delayed virus clearance, and persistent systemic inflammation in patients with severe COVID-19. Based on the concept of drug reposition, we review which antiviral or anti-inflammatory drugs can effectively treat COVID-19 patients based on progressive symptoms and the mechanisms inhibiting virus infection and replication.     

Identification of Entry Inhibitors against Delta and Omicron Variants of SARS-CoV-2

Entry inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed to control the outbreak of coronavirus disease 2019 (COVID-19). This study developed a robust and straightforward assay that detected the molecular interaction between the receptor-binding domain (RBD) of viral spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor in just 10 min. A drug library of 1068 approved compounds was used to screen for SARS-CoV2 entry inhibition, and 9 active drugs were identified as specific pseudovirus entry inhibitors. A plaque reduction neutralization test using authentic SARS-CoV-2 virus in Vero E6 cells confirmed that 2 of these drugs (Etravirine and Dolutegravir) significantly inhibited the infection of SARS-CoV-2. With molecular docking, we showed that both Etravirine and Dolutegravir are preferentially bound to primary ACE2-interacting residues on the RBD domain, implying that these two drug blocks may prohibit the viral attachment of SARS-CoV-2. We compared the neutralizing activities of these entry inhibitors against different pseudoviruses carrying spike proteins from alpha, beta, gamma, and delta variants. Both Etravirine and Dolutegravir showed similar neutralizing activities against different variants, with EC50 values between 4.5 to 5.8 nM for Etravirine and 10.2 to 22.9 nM for Dolutegravir. These data implied that Etravirine and Dolutegravir may serve as general spike inhibitors against dominant viral variants of SARS-CoV-2.     

Opportunities,Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19 †

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ⁹-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19.     

Kidney Injury in COVID-19: Epidemiology,Molecular Mechanisms and Potential Therapeutic Targets

As of December 2021, SARS-CoV-2 had caused over 250 million infections and 5 million deaths worldwide. Furthermore, despite the development of highly effective vaccines, novel variants of SARS-CoV-2 continue to sustain the pandemic, and the search for effective therapies for COVID-19 remains as urgent as ever. Though the primary manifestation of COVID-19 is pneumonia, the disease can affect multiple organs, including the kidneys, with acute kidney injury (AKI) being among the most common extrapulmonary manifestations of severe COVID-19. In this article, we start by reflecting on the epidemiology of kidney disease in COVID-19, which overwhelmingly demonstrates that AKI is common in COVID-19 and is strongly associated with poor outcomes. We also present emerging data showing that COVID-19 may result in long-term renal impairment and delve into the ongoing debate about whether AKI in COVID-19 is mediated by direct viral injury. Next, we focus on the molecular pathogenesis of SARS-CoV-2 infection by both reviewing previously published data and presenting some novel data on the mechanisms of cellular viral entry. Finally, we relate these molecular mechanisms to a series of therapies currently under investigation and propose additional novel therapeutic targets for COVID-19.     

Viral Infection and Cardiovascular Disease: Implications for the Molecular Basis of COVID-19 Pathogenesis

The current pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While this respiratory virus only causes mild symptoms in younger healthy individuals, elderly people and those with cardiovascular diseases such as systemic hypertension are susceptible to developing severe conditions that can be fatal. SARS-CoV-2 infection is also associated with an increased incidence of cardiovascular diseases such as myocardial injury, acute coronary syndrome, and thromboembolism. Understanding the mechanisms of the effects of this virus on the cardiovascular system should thus help develop therapeutic strategies to reduce the mortality and morbidity associated with SARS-CoV-2 infection. Since this virus causes severe and fatal conditions in older individuals with cardiovascular comorbidities, effective therapies targeting specific populations will likely contribute to ending this pandemic. In this review article, the effects of various viruses—including other coronaviruses, influenza, dengue, and human immunodeficiency virus—on the cardiovascular system are described to help provide molecular mechanisms of pathologies associated with SARS-CoV-2 infection and COVID-19. The goal is to provide mechanistic information from the biology of other viral infections in relation to cardiovascular pathologies for the purpose of developing improved vaccines and therapeutic agents effective in preventing and/or treating the acute and long-term consequences of SARS-CoV-2 and COVID-19.     

Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.     

Understanding the Pharmacology of COVID-19 mRNA Vaccines: Playing Dice with the Spike?

Coronavirus disease-19 (COVID-19) mRNA vaccines are the mainstays of mass vaccination campaigns in most Western countries. However, the emergency conditions in which their development took place made it impossible to fully characterize their effects and mechanism of action. Here, we summarize and discuss available evidence indicating that COVID-19 mRNA vaccines better reflect pharmaceutical drugs than conventional vaccines, as they do not contain antigens but an active SARS-CoV-2 S protein mRNA, representing at the same time an active principle and a prodrug, which upon intracellular translation results in the endogenous production of the SARS-CoV-2 S protein. Both vaccine-derived SARS-CoV-2 S protein mRNA and the resulting S protein exhibit a complex pharmacology and undergo systemic disposition. Defining COVID-19 mRNA vaccines as pharmaceutical drugs has straightforward implications for their pharmacodynamic, pharmacokinetic, clinical and post-marketing safety assessment. Only an accurate characterization of COVID-19 mRNA vaccines as pharmaceutical drugs will guarantee a safe, rational and individualized use of these products.     

Immunomodulation of Mesenchymal Stem Cells in Acute Lung Injury: From Preclinical Animal Models to Treatment of Severe COVID-19

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health challenge worldwide. Owing to the emergence of novel viral variants, the risks of reinfections and vaccine breakthrough infections has increased considerably despite a mass of vaccination. The formation of cytokine storm, which subsequently leads to acute respiratory distress syndrome, is the major cause of mortality in patients with COVID-19. Based on results of preclinical animal models and clinical trials of acute lung injury and acute respiratory distress syndrome, the immunomodulatory, tissue repair, and antiviral properties of MSCs highlight their potential to treat COVID-19. This review article summarizes the potential mechanisms and outcomes of MSC therapy in COVID-19, along with the pathogenesis of the SARS-CoV-2 infection. The properties of MSCs and lessons from preclinical animal models of acute lung injury are mentioned ahead. Important issues related to the use of MSCs in COVID-19 are discussed finally.     

Corticosteroids for COVID-19 Therapy: Potential Implications on Tuberculosis

On 11 March 2020, the World Health Organization announced the Corona Virus Disease-2019 (COVID-19) as a global pandemic, which originated in China. At the host level, COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), affects the respiratory system, with the clinical symptoms ranging from mild to severe or critical illness that often requires hospitalization and oxygen support. There is no specific therapy for COVID-19, as is the case for any common viral disease except drugs to reduce the viral load and alleviate the inflammatory symptoms. Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), also primarily affects the lungs and has clinical signs similar to pulmonary SARS-CoV-2 infection. Active TB is a leading killer among infectious diseases and adds to the burden of the COVID-19 pandemic worldwide. In immunocompetent individuals, primary Mtb infection can also lead to a non-progressive, asymptomatic latency. However, latent Mtb infection (LTBI) can reactivate symptomatic TB disease upon host immune-suppressing conditions. Importantly, the diagnosis and treatment of TB are hampered and admixed with COVID-19 control measures. The US-Center for Disease Control (US-CDC) recommends using antiviral drugs, Remdesivir or corticosteroid (CST), such as dexamethasone either alone or in-combination with specific recommendations for COVID-19 patients requiring hospitalization or oxygen support. However, CSTs can cause immunosuppression, besides their anti-inflammatory properties. The altered host immunity during COVID-19, combined with CST therapy, poses a significant risk for new secondary infections and/or reactivation of existing quiescent infections, such as LTBI. This review highlights CST therapy recommendations for COVID-19, various types and mechanisms of action of CSTs, the deadly combination of two respiratory infectious diseases COVID-19 and TB. It also discusses the importance of screening for LTBI to prevent TB reactivation during corticosteroid therapy for COVID-19.     

Human Milk Antibodies against S1 and S2 Subunits from SARS-CoV-2, HCoV-OC43, and HCoV-229E in Mothers with a Confirmed COVID-19 PCR,Viral SYMPTOMS,and Unexposed Mothers

Background: Preexisting immunity to SARS-CoV-2 could be related to cross-reactive antibodies to common human-coronaviruses (HCoVs). This study aimed to evaluate whether human milk antibodies against to S1 and S2 subunits SARS-CoV-2 are cross-reactive to S1 and S2 subunits HCoV-OC43 and HCoV-229E in mothers with a confirmed COVID-19 PCR test, in mothers with previous viral symptoms during COVID-19 pandemic, and in unexposed mothers; Methods: The levels of secretory IgA (SIgA)/IgA, secretory IgM (SIgM)/IgM, and IgG specific to S1 and S2 SARS-CoV-2, and reactive to S1 + S2 HCoV-OC43, and HCoV-229E were measured in milk from 7 mothers with a confirmed COVID-19 PCR test, 20 mothers with viral symptoms, and unexposed mothers (6 Ctl1-2018 and 16 Ctl2-2018) using ELISA; Results: The S2 SARS-CoV-2 IgG levels were higher in the COVID-19 PCR (p = 0.014) and viral symptom (p = 0.040) groups than in the Ctl1-2018 group. We detected a higher number of positive correlations between the antigens and secretory antibodies in the COVID-19 PCR group than in the viral symptom and Ctl-2018 groups. S1 + S2 HCoV-OC43-reactive IgG was higher in the COVID-19 group than in the control group (p = 0.002) but did not differ for the other antibodies; Conclusions: Mothers with a confirmed COVID-19 PCR and mothers with previous viral symptoms had preexisting human milk antibodies against S2 subunit SARS-CoV-2. Human milk IgG were more specific to S2 subunit SARS-CoV-2 than other antibodies, whereas SIgA and SIgM were polyreactive and cross-reactive to S1 or S2 subunit SARS-CoV-2.     

Newly Emerged Antiviral Strategies for SARS-CoV-2: From Deciphering Viral Protein Structural Function to the Development of Vaccines,Antibodies, and Small Molecules

Coronavirus disease 2019 (COVID-19) caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the most severe health crisis, causing extraordinary economic disruption worldwide. SARS-CoV-2 is a single-stranded RNA-enveloped virus. The process of viral replication and particle packaging is finished in host cells. Viral proteins, including both structural and nonstructural proteins, play important roles in the viral life cycle, which also provides the targets of treatment. Therefore, a better understanding of the structural function of virus proteins is crucial to speed up the development of vaccines and therapeutic strategies. Currently, the structure and function of proteins encoded by the SARS-CoV-2 genome are reviewed by several studies. However, most of them are based on the analysis of SARS-CoV-1 particles, lacking a systematic review update for SARS-CoV-2. Here, we specifically focus on the structure and function of proteins encoded by SARS-CoV-2. Viral proteins that contribute to COVID-19 infection and disease pathogenesis are reviewed according to the most recent research findings. The structure-function correlation of viral proteins provides a fundamental rationale for vaccine development and targeted therapy. Then, current antiviral vaccines are updated, such as inactive viral vaccines and protein-based vaccines and DNA, mRNA, and circular RNA vaccines. A summary of other therapeutic options is also reviewed, including monoclonal antibodies such as a cross-neutralizer antibody, a constructed cobinding antibody, a dual functional monoclonal antibody, an antibody cocktail, and an engineered bispecific antibody, as well as peptide-based inhibitors, chemical compounds, and clustered regularly interspaced short palindromic repeats (CRISPR) exploration. Overall, viral proteins and their functions provide the basis for targeted therapy and vaccine development.     

Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern

The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid^® and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study.     

Emerging Advances of Nanotechnology in Drug and Vaccine Delivery against Viral Associated Respiratory Infectious Diseases (VARID)

Viral-associated respiratory infectious diseases are one of the most prominent subsets of respiratory failures, known as viral respiratory infections (VRI). VRIs are proceeded by an infection caused by viruses infecting the respiratory system. For the past 100 years, viral associated respiratory epidemics have been the most common cause of infectious disease worldwide. Due to several drawbacks of the current anti-viral treatments, such as drug resistance generation and non-targeting of viral proteins, the development of novel nanotherapeutic or nano-vaccine strategies can be considered essential. Due to their specific physical and biological properties, nanoparticles hold promising opportunities for both anti-viral treatments and vaccines against viral infections. Besides the specific physiological properties of the respiratory system, there is a significant demand for utilizing nano-designs in the production of vaccines or antiviral agents for airway-localized administration. SARS-CoV-2, as an immediate example of respiratory viruses, is an enveloped, positive-sense, single-stranded RNA virus belonging to the coronaviridae family. COVID-19 can lead to acute respiratory distress syndrome, similarly to other members of the coronaviridae. Hence, reviewing the current and past emerging nanotechnology-based medications on similar respiratory viral diseases can identify pathways towards generating novel SARS-CoV-2 nanotherapeutics and/or nano-vaccines.     

Theophylline: Old Drug in a New Light,Application in COVID-19 through Computational Studies

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.     

Metal Complexes as Antiviral Agents for SARS-CoV-2

The severe acute respiratory syndrome – coronavirus 2 (SARS-CoV-2), the infectious agent responsible for COVID-19 – has caused more than 2.5 million deaths worldwide and triggered a global pandemic. Even with successful vaccines being delivered, there is an urgent need for novel treatments to combat SARS-CoV-2, and other emerging viral diseases. While several organic small molecule drug candidates are in development, some effort has also been devoted towards the application of metal complexes as potential antiviral agents against SARS-CoV-2. Herein, the metal complexes that have been reported to show antiviral activity against SARS-CoV-2 or one of its target proteins are described and their proposed mechanisms of action are discussed.