Potential COVID-19 Therapies from Computational Repurposing of Drugs and Natural Products against the SARS-CoV-2 Helicase

Repurposing of existing drugs is a rapid way to find potential new treatments for SARS-CoV-2. Here, we applied a virtual screening approach using Autodock Vina and molecular dynamic simulation in tandem to screen and calculate binding energies of repurposed drugs against the SARS-CoV-2 helicase protein (non-structural protein nsp13). Amongst the top hits from our study were antivirals, antihistamines, and antipsychotics, plus a range of other drugs. Approximately 30% of our top 87 hits had published evidence indicating in vivo or in vitro SARS-CoV-2 activity. Top hits not previously reported to have SARS-CoV-2 activity included the antiviral agents, cabotegravir and RSV-604; the NK1 antagonist, aprepitant; the trypanocidal drug, aminoquinuride; the analgesic, antrafenine; the anticancer intercalator, epirubicin; the antihistamine, fexofenadine; and the anticoagulant, dicoumarol. These hits from our in silico SARS-CoV-2 helicase screen warrant further testing as potential COVID-19 treatments.     

Developing New Treatments for COVID-19 through Dual-Action Antiviral/Anti-Inflammatory Small Molecules and Physiologically Based Pharmacokinetic Modeling

Broad-spectrum antiviral agents that are effective against many viruses are difficult to develop, as the key molecules, as well as the biochemical pathways by which they cause infection, differ largely from one virus to another. This was more strongly highlighted by the COVID-19 pandemic, which found health systems all over the world largely unprepared and proved that the existing armamentarium of antiviral agents is not sufficient to address viral threats with pandemic potential. The clinical protocols for the treatment of COVID-19 are currently based on the use of inhibitors of the inflammatory cascade (dexamethasone, baricitinib), or inhibitors of the cytopathic effect of the virus (monoclonal antibodies, molnupiravir or nirmatrelvir/ritonavir), using different agents. There is a critical need for an expanded armamentarium of orally bioavailable small-molecular medicinal agents, including those that possess dual antiviral and anti-inflammatory (AAI) activity that would be readily available for the early treatment of mild to moderate COVID-19 in high-risk patients. A multidisciplinary approach that involves the use of in silico screening tools to identify potential drug targets of an emerging pathogen, as well as in vitro and in vivo models for the determination of a candidate drug’s efficacy and safety, are necessary for the rapid and successful development of antiviral agents with potentially dual AAI activity. Characterization of candidate AAI molecules with physiologically based pharmacokinetics (PBPK) modeling would provide critical data for the accurate dosing of new therapeutic agents against COVID-19. This review analyzes the dual mechanisms of AAI agents with potential anti-SARS-CoV-2 activity and discusses the principles of PBPK modeling as a conceptual guide to develop new pharmacological modalities for the treatment of COVID-19.     

The Endothelium and COVID-19: An Increasingly Clear Link Brief Title: Endotheliopathy in COVID-19

The endothelium has a fundamental role in the cardiovascular complications of coronavirus disease 2019 (COVID-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) particularly affects endothelial cells. The virus binds to the angiotensin-converting enzyme 2 (ACE-2) receptor (present on type 2 alveolar cells, bronchial epithelial cells, and endothelial cells), and induces a cytokine storm. The cytokines tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 have particular effects on endothelial cells—leading to endothelial dysfunction, endothelial cell death, changes in tight junctions, and vascular hyperpermeability. Under normal conditions, apoptotic endothelial cells are removed into the bloodstream. During COVID-19, however, endothelial cells are detached more rapidly, and do not regenerate as effectively as usual. The loss of the endothelium on the luminal surface abolishes all of the vascular responses mediated by the endothelium and nitric oxide production in particular, which results in greater contractility. Moreover, circulating endothelial cells infected with SARS-CoV-2 act as vectors for viral dissemination by forming clusters that migrate into the circulation and reach distant organs. The cell clusters and the endothelial dysfunction might contribute to the various thromboembolic pathologies observed in COVID-19 by inducing the formation of intravascular microthrombi, as well as by triggering disseminated intravascular coagulation. Here, we review the contributions of endotheliopathy and endothelial-cell-derived extracellular vesicles to the pathogenesis of COVID-19, and discuss therapeutic strategies that target the endothelium in patients with COVID-19.     

Identification of 13 Guanidinobenzoyl- or Aminidinobenzoyl-Containing Drugs to Potentially Inhibit TMPRSS2 for COVID-19 Treatment

Positively charged groups that mimic arginine or lysine in a natural substrate of trypsin are necessary for drugs to inhibit the trypsin-like serine protease TMPRSS2 that is involved in the viral entry and spread of coronaviruses, including SARS-CoV-2. Based on this assumption, we identified a set of 13 approved or clinically investigational drugs with positively charged guanidinobenzoyl and/or aminidinobenzoyl groups, including the experimentally verified TMPRSS2 inhibitors Camostat and Nafamostat. Molecular docking using the C-I-TASSER-predicted TMPRSS2 catalytic domain model suggested that the guanidinobenzoyl or aminidinobenzoyl group in all the drugs could form putative salt bridge interactions with the side-chain carboxyl group of Asp435 located in the S1 pocket of TMPRSS2. Molecular dynamics simulations further revealed the high stability of the putative salt bridge interactions over long-time (100 ns) simulations. The molecular mechanics/generalized Born surface area-binding free energy assessment and per-residue energy decomposition analysis also supported the strong binding interactions between TMPRSS2 and the proposed drugs. These results suggest that the proposed compounds, in addition to Camostat and Nafamostat, could be effective TMPRSS2 inhibitors for COVID-19 treatment by occupying the S1 pocket with the hallmark positively charged groups.     

Existing Drugs Considered as Promising in COVID-19 Therapy

COVID-19 is a respiratory disease caused by newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease at first was identified in the city of Wuhan, China in December 2019. Being a human infectious disease, it causes high fever, cough, breathing problems. In some cases it can be fatal, especially in people with comorbidities like heart or kidney problems and diabetes. The current COVID-19 treatment is based on symptomatic therapy, so finding an appropriate drug against COVID-19 remains an immediate and crucial target for the global scientific community. Two main processes are thought to be responsible for the COVID-19 pathogenesis. In the early stages of infection, disease is determined mainly by virus replication. In the later stages of infection, by an excessive immune/inflammatory response, leading to tissue damage. Therefore, the main treatment options are antiviral and immunomodulatory/anti-inflammatory agents. Many clinical trials have been conducted concerning the use of various drugs in COVID-19 therapy, and many are still ongoing. The majority of trials examine drug reposition (repurposing), which seems to be a good and effective option. Many drugs have been repurposed in COVID-19 therapy including remdesivir, favipiravir, tocilizumab and baricitinib. The aim of this review is to highlight (based on existing and accessible clinical evidence on ongoing trials) the current and available promising drugs for COVID-19 and outline their characteristics.     

The Role of P-Selectin in COVID-19 Coagulopathy: An Updated Review

In severe COVID-19, which is characterized by blood clots and neutrophil-platelet aggregates in the circulating blood and different tissues, an increased incidence of cardiovascular complications and venous thrombotic events has been reported. The inflammatory storm that characterizes severe infections may act as a driver capable of profoundly disrupting the complex interplay between platelets, endothelium, and leukocytes, thus contributing to the definition of COVID-19-associated coagulopathy. In this frame, P-selectin represents a key molecule expressed on endothelial cells and on activated platelets, and contributes to endothelial activation, leucocyte recruitment, rolling, and tissue migration. Briefly, we describe the current state of knowledge about P-selectin involvement in COVID-19 pathogenesis, its possible use as a severity marker and as a target for host-directed therapeutic intervention.     

Adaptive Immunity and the Risk of Autoreactivity in COVID-19

While first and foremost considered a respiratory infection, COVID-19 can result in complications affecting multiple organs. Immune responses in COVID-19 can both protect against the disease as well as drive it. Insights into these responses, and specifically the targets being recognised by the immune system, are of vital importance in understanding the side effects of COVID-19 and associated pathologies. The body’s adaptive immunity recognises and responds against specific targets (antigens) expressed by foreign pathogens, but not usually to target self-antigens. However, if the immune system becomes dysfunctional, adaptive immune cells can react to self-antigens, which can result in autoimmune disease. Viral infections are well reported to be associated with, or exacerbate, autoimmune diseases such as multiple sclerosis (MS) and systemic lupus erythematosus (SLE). In COVID-19 patients, both new onset MS and SLE, as well as the occurrence of other autoimmune-like pathologies, have been reported. Additionally, the presence of autoantibodies, both with and without known associations to autoimmune diseases, have been found. Herein we describe the mechanisms of virally induced autoimmunity and summarise some of the emerging reports on the autoimmune-like diseases and autoreactivity that is reported to be associated with SARS-CoV-2 infection.     

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.     

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.     

In Silico Molecular Dynamics of Griseofulvin and Its Derivatives Revealed Potential Therapeutic Applications for COVID-19

Treatment options for Coronavirus Disease 2019 (COVID-19) remain limited, and the option of repurposing approved drugs with promising medicinal properties is of increasing interest in therapeutic approaches to COVID-19. Using computational approaches, we examined griseofulvin and its derivatives against four key anti-SARS-CoV-2 targets: main protease, RdRp, spike protein receptor-binding domain (RBD), and human host angiotensin-converting enzyme 2 (ACE2). Molecular docking analysis revealed that griseofulvin (CID 441140) has the highest docking score (–6.8 kcal/mol) with main protease of SARS-CoV-2. Moreover, griseofulvin derivative M9 (CID 144564153) proved the most potent inhibitor with −9.49 kcal/mol, followed by A3 (CID 46844082) with −8.44 kcal/mol against M protease and ACE2, respectively. Additionally, H bond analysis revealed that compound A3 formed the highest number of hydrogen bonds, indicating the strongest inhibitory efficacy against ACE2. Further, molecular dynamics (MD) simulation analysis revealed that griseofulvin and these derivatives are structurally stable. These findings suggest that griseofulvin and its derivatives may be considered when designing future therapeutic options for SARS-CoV-2 infection.     

A Review: Highlighting the Links between Epigenetics,COVID-19 Infection,and Vitamin D

The highly transmittable and infectious COVID-19 remains a major threat worldwide, with the elderly and comorbid individuals being the most vulnerable. While vaccines are currently available, therapeutic drugs will help ease the viral outbreak and prevent serious health outcomes. Epigenetic modifications regulate gene expression through changes in chromatin structure and have been linked to viral pathophysiology. Since epigenetic modifications contribute to the life cycle of the virus and host immune responses to infection, epigenetic drugs are promising treatment targets to ameliorate COVID-19. Deficiency of the multifunctional secosteroid hormone vitamin D is a global health threat. Vitamin D and its receptor function to regulate genes involved in immunity, apoptosis, proliferation, differentiation, and inflammation. Amassed evidence also indicates the biological relations of vitamin D with reduced disease risk, while its receptor can be modulated by epigenetic mechanisms. The immunomodulatory effects of vitamin D suggest a role for vitamin D as a COVID-19 therapeutic agent. Therefore, this review highlights the epigenetic effects on COVID-19 and vitamin D while also proposing a role for vitamin D in COVID-19 infections.     

Alveolar Regeneration in COVID-19 Patients: A Network Perspective

A viral infection involves entry and replication of viral nucleic acid in a host organism, subsequently leading to biochemical and structural alterations in the host cell. In the case of SARS-CoV-2 viral infection, over-activation of the host immune system may lead to lung damage. Albeit the regeneration and fibrotic repair processes being the two protective host responses, prolonged injury may lead to excessive fibrosis, a pathological state that can result in lung collapse. In this review, we discuss regeneration and fibrosis processes in response to SARS-CoV-2 and provide our viewpoint on the triggering of alveolar regeneration in coronavirus disease 2019 (COVID-19) patients.     

Molecular Networking for Drug Toxicities Studies: The Case of Hydroxychloroquine in COVID-19 Patients

Using drugs to treat COVID-19 symptoms may induce adverse effects and modify patient outcomes. These adverse events may be further aggravated in obese patients, who often present different illnesses such as metabolic-associated fatty liver disease. In Rennes University Hospital, several drug such as hydroxychloroquine (HCQ) have been used in the clinical trial HARMONICOV to treat COVID-19 patients, including obese patients. The aim of this study is to determine whether HCQ metabolism and hepatotoxicity are worsened in obese patients using an in vivo/in vitro approach. Liquid chromatography high resolution mass spectrometry in combination with untargeted screening and molecular networking were employed to study drug metabolism in vivo (patient’s plasma) and in vitro (HepaRG cells and RPTEC cells). In addition, HepaRG cells model were used to reproduce pathophysiological features of obese patient metabolism, i.e., in the condition of hepatic steatosis. The metabolic signature of HCQ was modified in HepaRG cells cultured under a steatosis condition and a new metabolite was detected (carboxychloroquine). The RPTEC model was found to produce only one metabolite. A higher cytotoxicity of HCQ was observed in HepaRG cells exposed to exogenous fatty acids, while neutral lipid accumulation (steatosis) was further enhanced in these cells. These in vitro data were compared with the biological parameters of 17 COVID-19 patients treated with HCQ included in the HARMONICOV cohort. Overall, our data suggest that steatosis may be a risk factor for altered drug metabolism and possibly toxicity of HCQ.     

Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at −8.3 kcal/mol, followed by Zn and Ca at −8.0 kcal/mol, and Fe and Mg at −7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn–Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.     

Anti-SARS-CoV-2 Strategies and the Potential Role of miRNA in the Assessment of COVID-19 Morbidity,Recurrence, and Therapy

Recently, we have experienced a serious pandemic. Despite significant technological advances in molecular technologies, it is very challenging to slow down the infection spread. It appeared that due to globalization, SARS-CoV-2 spread easily and adapted to new environments or geographical or weather zones. Additionally, new variants are emerging that show different infection potential and clinical outcomes. On the other hand, we have some experience with other pandemics and some solutions in virus elimination that could be adapted. This is of high importance since, as the latest reports demonstrate, vaccine technology might not follow the new, mutated virus outbreaks. Thus, identification of novel strategies and markers or diagnostic methods is highly necessary. For this reason, we present some of the latest views on SARS-CoV-2/COVID-19 therapeutic strategies and raise a solution based on miRNA. We believe that in the face of the rapidly increasing global situation and based on analogical studies of other viruses, the possibility of using the biological potential of miRNA technology is very promising. It could be used as a promising diagnostic and prognostic factor, as well as a therapeutic target and tool.     

Immune-Modulating Drug MP1032 with SARS-CoV-2 Antiviral Activity In Vitro: A potential Multi-Target Approach for Prevention and Early Intervention Treatment of COVID-19

At least since March 2020, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic and the multi-organ coronavirus disease 2019 (COVID-19) are keeping a firm grip on the world. Although most cases are mild, older patients and those with co-morbidities are at increased risk of developing a cytokine storm, characterized by a systemic inflammatory response leading to acute respiratory distress syndrome and organ failure. The present paper focuses on the small molecule MP1032, describes its mode of action, and gives rationale why it is a promising option for the prevention/treatment of the SARS-CoV-2-induced cytokine storm. MP1032 is a phase-pure anhydrous polymorph of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt that exhibits good stability and bioavailability. The physiological action of MP1032 is based on a multi-target mechanism including localized, self-limiting reactive oxygen species (ROS) scavenging activities that were demonstrated in a model of lipopolysaccharide (LPS)-induced joint inflammation. Furthermore, its immune-regulatory and PARP-1-modulating properties, coupled with antiviral effects against SARS-CoV-2, have been demonstrated in various cell models. Preclinical efficacy was elucidated in LPS-induced endotoxemia, a model with heightened innate immune responses that shares many similarities to COVID-19. So far, during oral clinical development with three-month daily administrations, no serious adverse drug reactions occurred, highlighting the outstanding safety profile of MP1032.     

Venous Thromboembolic Disease in COVID-19, Pathophysiology,Therapy and Prophylaxis

For over two years, the world has been facing the epidemiological and health challenge of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Growing problems are also complications after the development of COVID-19 in the form of post and long- COVID syndromes, posing a challenge for the medical community, both for clinicians and the scientific world. SARS-CoV-2 infection is associated with an increased risk of cardiovascular complications, especially thromboembolic complications, which are associated with both thrombosis of small and very small vessels due to immunothrombosis, and the development of venous thromboembolism. Low molecular wight heparin (LMHW) are the basic agents used in the prevention and treatment of thromboembolic complications in COVID-19. There is still a great deal of controversy regarding both the prevention and treatment of thromboembolic complications, including the prophylaxis dose or the optimal duration of anticoagulant treatment in patients with an episode of venous thromboembolism.     

Whey-Derived Peptides at the Heart of the COVID-19 Pandemic

The renin–angiotensin system (RAS) is a key regulator of blood pressure and hypertension. Angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme I (ACE) are two main components of the RAS that play a major role in blood pressure homeostasis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 as a receptor to enter cells. Despite some controversies, numerous studies have reported a significant association between the use of ACE inhibitors and reduced risk of COVID-19. In our previous studies, we produced and identified peptide sequences present in whey hydrolysates exhibiting high ACE inhibitory activity. Therefore, the aim of this work is to obtain an improved understanding of the function of these natural peptides as RAS inhibitors and investigate their potential therapeutic role in the COVID-19 pandemic. The molecular interactions between peptides IPP, LIVTQ, IIAE, LVYPFP, and human ACE2 were assessed by employing a molecular docking approach. The results show that natural whey-derived peptides have a dual inhibitory action against both ACE and ACE2. This dual activity distinguishes these ACE inhibitory peptides from synthetic drugs, such as Captopril and Lisinopril which were not shown to inhibit ACE2 activity, and may represent a potential strategy in the treatment of COVID-19.     

Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology

The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a “magic bullet” drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention.     

Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality across the world, with no current effective treatments available. Recent studies suggest the possibility of a cytokine storm associated with severe COVID-19, similar to the biochemical profile seen in hemophagocytic lymphohistiocytosis (HLH), raising the question of possible benefits that could be derived from targeted immunosuppression in severe COVID-19 patients. We reviewed the literature regarding the diagnosis and features of HLH, particularly secondary HLH, and aimed to identify gaps in the literature to truly clarify the existence of a COVID-19 associated HLH. Diagnostic criteria such as HScore or HLH-2004 may have suboptimal performance in identifying COVID-19 HLH-like presentations, and criteria such as soluble CD163, NK cell activity, or other novel biomarkers may be more useful in identifying this entity.