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1.
ACS Nano ; 14(8): 9364-9388, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-646861

ABSTRACT

The SARS-Cov-2 pandemic has spread worldwide during 2020, setting up an uncertain start of this decade. The measures to contain infection taken by many governments have been extremely severe by imposing home lockdown and industrial production shutdown, making this the biggest crisis since the second world war. Additionally, the continuous colonization of wild natural lands may touch unknown virus reservoirs, causing the spread of epidemics. Apart from SARS-Cov-2, the recent history has seen the spread of several viral pandemics such as H2N2 and H3N3 flu, HIV, and SARS, while MERS and Ebola viruses are considered still in a prepandemic phase. Hard nanomaterials (HNMs) have been recently used as antimicrobial agents, potentially being next-generation drugs to fight viral infections. HNMs can block infection at early (disinfection, entrance inhibition) and middle (inside the host cells) stages and are also able to mitigate the immune response. This review is focused on the application of HNMs as antiviral agents. In particular, mechanisms of actions, biological outputs, and limitations for each HNM will be systematically presented and analyzed from a material chemistry point-of-view. The antiviral activity will be discussed in the context of the different pandemic viruses. We acknowledge that HNM antiviral research is still at its early stage, however, we believe that this field will rapidly blossom in the next period.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/therapy , Nanostructures/therapeutic use , Pandemics , Pneumonia, Viral/therapy , Adaptive Immunity , Betacoronavirus/drug effects , Betacoronavirus/physiology , Betacoronavirus/ultrastructure , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Delivery Systems , Fullerenes/therapeutic use , Host Microbial Interactions/drug effects , Humans , Immunity, Innate , Metal Nanoparticles/therapeutic use , Models, Biological , Nanotechnology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Reactive Oxygen Species/therapeutic use , Virus Internalization/drug effects
2.
Nano Lett ; 20(7): 5367-5375, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-628240

ABSTRACT

Geometry-matching has been known to benefit the formation of stable biological interactions in natural systems. Herein, we report that the spiky nanostructures with matched topography to the influenza A virus (IAV) virions could be used to design next-generation advanced virus inhibitors. We demonstrated that nanostructures with spikes between 5 and 10 nm bind significantly better to virions than smooth nanoparticles, due to the short spikes inserting into the gaps of glycoproteins of the IAV virion. Furthermore, an erythrocyte membrane (EM) was coated to target the IAV, and the obtained EM-coated nanostructures could efficiently prevent IAV virion binding to the cells and inhibit subsequent infection. In a postinfection study, the EM-coated nanostructures reduced >99.9% virus replication at the cellular nontoxic dosage. We predict that such a combination of geometry-matching topography and cellular membrane coating will also push forward the development of nanoinhibitors for other virus strains, including SARS-CoV-2.


Subject(s)
Betacoronavirus/ultrastructure , Coronavirus Infections/virology , Nanostructures/ultrastructure , Pneumonia, Viral/virology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Binding Sites , Coronavirus Infections/drug therapy , Drug Design , Humans , Influenza A virus/drug effects , Influenza A virus/ultrastructure , Microscopy, Electron , Models, Biological , Nanotechnology , Pandemics , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/drug effects , Spike Glycoprotein, Coronavirus/ultrastructure , Virus Internalization/drug effects
3.
Cell Physiol Biochem ; 54(4): 767-790, 2020 Aug 25.
Article in English | MEDLINE | ID: covidwho-729851

ABSTRACT

The pandemic of the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 at the end of 2019 marked the third outbreak of a highly pathogenic coronavirus affecting the human population in the past twenty years. Cross-species zoonotic transmission of SARS-CoV-2 has caused severe pathogenicity and led to more than 655,000 fatalities worldwide until July 28, 2020. Outbursts of this virus underlined the importance of controlling infectious pathogens across international frontiers. Unfortunately, there is currently no clinically approved antiviral drug or vaccine against SARS-CoV-2, although several broad-spectrum antiviral drugs targeting multiple RNA viruses have shown a positive response and improved recovery in patients. In this review, we compile our current knowledge of the emergence, transmission, and pathogenesis of SARS-CoV-2 and explore several features of SARS-CoV-2. We emphasize the current therapeutic approaches used to treat infected patients. We also highlight the results of in vitro and in vivo data from several studies, which have broadened our knowledge of potential drug candidates for the successful treatment of patients infected with and discuss possible virus and host-based treatment options against SARS-CoV-2.


Subject(s)
Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/genetics , Betacoronavirus/physiology , Coronaviridae/pathogenicity , Coronaviridae Infections/epidemiology , Coronaviridae Infections/virology , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Coronavirus Infections/transmission , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Cytokines/antagonists & inhibitors , Drug Delivery Systems , Endocytosis/drug effects , Forecasting , Genome, Viral , Global Health , Humans , Immunity, Herd , Immunization, Passive , Pandemics/prevention & control , Peptide Hydrolases/pharmacology , Peptide Hydrolases/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , RNA, Viral/genetics , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Viral Vaccines , Virus Internalization/drug effects , Virus Replication/drug effects , Zoonoses
4.
Molecules ; 25(17)2020 Aug 22.
Article in English | MEDLINE | ID: covidwho-727433

ABSTRACT

Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/drug effects , Cathepsin L/chemistry , Phytochemicals/chemistry , Protease Inhibitors/chemistry , Receptors, Virus/chemistry , Serine Endopeptidases/chemistry , Amino Acid Sequence , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Betacoronavirus/pathogenicity , Binding Sites , Cathepsin L/antagonists & inhibitors , Cathepsin L/genetics , Cathepsin L/metabolism , Coronavirus Infections/drug therapy , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Coumarins/chemistry , Coumarins/isolation & purification , Coumarins/pharmacology , Gene Expression , High-Throughput Screening Assays , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , India , Molecular Docking Simulation , Molecular Dynamics Simulation , Monosaccharides/chemistry , Monosaccharides/isolation & purification , Monosaccharides/pharmacology , Pandemics , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Plants, Medicinal/chemistry , Pneumonia, Viral/drug therapy , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Protease Inhibitors/isolation & purification , Protease Inhibitors/pharmacology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Quinazolines/chemistry , Quinazolines/isolation & purification , Quinazolines/pharmacology , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/genetics , Receptors, Virus/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Thermodynamics , Virus Internalization/drug effects
5.
Front Immunol ; 11: 1664, 2020.
Article in English | MEDLINE | ID: covidwho-724205

ABSTRACT

The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) associated Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising molecules for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified molecules may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these molecules could save lives is justified.


Subject(s)
Betacoronavirus/physiology , Computer Simulation , Coronavirus Infections/drug therapy , Drug Repositioning/methods , Pneumonia, Viral/drug therapy , User-Computer Interface , Virus Internalization/drug effects , Anti-Inflammatory Agents/therapeutic use , Binding Sites , Coronavirus Infections/virology , Genome, Viral/genetics , Humans , Models, Genetic , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Protein Binding , Protein Domains , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry , Virus Attachment
6.
Int J Mol Sci ; 21(16)2020 Aug 09.
Article in English | MEDLINE | ID: covidwho-713065

ABSTRACT

The pandemic evolution of SARS-CoV-2 infection is forcing the scientific community to unprecedented efforts to explore all possible approaches against COVID-19. In this context, targeting virus entry is a promising antiviral strategy for controlling viral infections. The main strategies pursued to inhibit the viral entry are considering both the virus and the host factors involved in the process. Primarily, direct-acting antivirals rely on inhibition of the interaction between ACE2 and the receptor binding domain (RBD) of the Spike (S) protein or targeting the more conserved heptad repeats (HRs), involved in the membrane fusion process. The inhibition of host TMPRSS2 and cathepsins B/L may represent a complementary strategy to be investigated. In this review, we discuss the development entry inhibitors targeting the S protein, as well as the most promising host targeting strategies involving TMPRSS2 and CatB/L, which have been exploited so far against CoVs and other related viruses.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Serine Proteinase Inhibitors/pharmacology , Virus Internalization/drug effects , Animals , Betacoronavirus/metabolism , Betacoronavirus/physiology , Humans , Spike Glycoprotein, Coronavirus/metabolism
7.
Am J Physiol Cell Physiol ; 319(2): C244-C249, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-711625

ABSTRACT

The outbreak of COVID-19 pneumonia caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) is posing a global health emergency and has led to more than 380,000 deaths worldwide. The cell entry of SARS-CoV-2 depends on two host proteins angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). There is currently no vaccine available and also no effective drug for the treatment of COVID-19. Hydrogen sulfide (H2S) as a novel gasotransmitter has been shown to protect against lung damage via its anti-inflammation, antioxidative stress, antiviral, prosurvival, and antiaging effects. In light of the research advances on H2S signaling in biology and medicine, this review proposed H2S as a potential defense against COVID-19. It is suggested that H2S may block SARS-CoV-2 entry into host cells by interfering with ACE2 and TMPRSS2, inhibit SARS-CoV-2 replication by attenuating virus assembly/release, and protect SARS-CoV-2-induced lung damage by suppressing immune response and inflammation development. Preclinical studies and clinical trials with slow-releasing H2S donor(s) or the activators of endogenous H2S-generating enzymes should be considered as a preventative treatment or therapy for COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Hydrogen Sulfide/therapeutic use , Pneumonia, Viral/drug therapy , Virus Internalization/drug effects , Virus Replication/drug effects , Animals , Betacoronavirus/pathogenicity , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Hydrogen Sulfide/metabolism , Lung/drug effects , Lung/metabolism , Lung/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Serine Endopeptidases/metabolism , Signal Transduction
8.
Int J Antimicrob Agents ; 56(3): 106118, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-704750

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is rapidly advancing across the globe despite drastic public and personal health measures. Antivirals and nutritional supplements have been proposed as potentially useful against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes COVID-19, but few have been clinically established. Lactoferrin (Lf) is a naturally occurring, non-toxic glycoprotein that is orally available as a nutritional supplement and has established in vitro antiviral efficacy against a wide range of viruses, including SARS-CoV, a closely related coronavirus to SARS-CoV-2. Furthermore, Lf possesses unique immunomodulatory and anti-inflammatory effects that may be especially relevant to the pathophysiology of severe COVID-19 cases. Here we review the underlying biological mechanisms of Lf as an antiviral and immune regulator, and propose its unique potential as a preventative and adjunct treatment for COVID-19. We hope that further research and development of Lf nutritional supplementation would establish its role for COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Immunologic Factors/therapeutic use , Lactoferrin/therapeutic use , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Betacoronavirus/drug effects , Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Heparan Sulfate Proteoglycans/antagonists & inhibitors , Heparan Sulfate Proteoglycans/metabolism , Humans , Interferons/agonists , Interferons/biosynthesis , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , Severity of Illness Index , Virus Internalization/drug effects , Virus Replication/drug effects
9.
Cells ; 9(8)2020 08 11.
Article in English | MEDLINE | ID: covidwho-706247

ABSTRACT

The development of biological disease-modifying antirheumatic drugs (bDMARDs) and target synthetic DMARDs (tsDMARDs), also known as small molecule inhibitors, represent a breakthrough in rheumatoid arthritis (RA) treatment. The tsDMARDs are a large family of small molecules targeting mostly the several types of kinases, which are essential in downstream signaling of pro-inflammatory molecules. This review highlights current challenges associated with the treatment of RA using small molecule inhibitors targeting intracellular JAKs/MAPKs/NF-κB/SYK-BTK signaling pathways. Indeed, we have provided the latest update on development of small molecule inhibitors, their clinical efficacy and safety as a strategy for RA treatment. On the other hand, we have highlighted the risk and adverse effects of tsDMARDs administration including, among others, infections and thromboembolism. Therefore, performance of blood tests or viral infection screening should be recommended before the tsDMARDs administration. Interestingly, recent events of SARS-CoV-2 outbreak have demonstrated the potential use of small molecule inhibitors not only in RA treatment, but also in fighting COVID-19 via blocking the viral entry, preventing of hyperimmune activation and reducing cytokine storm. Thus, small molecule inhibitors, targeting wide range of pro-inflammatory singling pathways, may find wider implications not only for the management of RA but also in the controlling of COVID-19.


Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Betacoronavirus/drug effects , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/immunology , Cytokines/metabolism , Drug Therapy, Combination , Humans , Inflammation/immunology , Inflammation/metabolism , Mice , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Signal Transduction/drug effects , Treatment Outcome , Virus Internalization/drug effects
10.
Int J Antimicrob Agents ; 56(3): 106078, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-701532

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is having serious consequences on health and the economy worldwide. All evidence-based treatment strategies need to be considered to combat this new virus. Drugs need to be considered on scientific grounds of efficacy, safety and cost. Chloroquine (CQ) and hydroxychloroquine (HCQ) are old drugs used in the treatment of malaria. Moreover, their antiviral properties have been previously studied, including against coronaviruses, where evidence of efficacy has been found. In the current race against time triggered by the COVID-19 pandemic, the search for new antivirals is very important. However, consideration should be given to old drugs with known anti-coronavirus activity, such as CQ and HCQ. These could be integrated into current treatment strategies while novel treatments are awaited, also in light of the fact that they display an anticoagulant effect that facilitates the activity of low-molecular-weight heparin, aimed at preventing acute respiratory distress syndrome (ARDS)-associated thrombotic events. The safety of CQ and HCQ has been studied for over 50 years, however recently published data raise concerns for cardiac toxicity of CQ/HCQ in patients with COVID-19. This review also re-examines the real information provided by some of the published alarming reports, although concluding that cardiac toxicity should in any case be stringently monitored in patients receiving CQ/HCQ.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/prevention & control , Disseminated Intravascular Coagulation/prevention & control , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Autophagy/drug effects , Autophagy/genetics , Betacoronavirus/growth & development , Betacoronavirus/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Disseminated Intravascular Coagulation/virology , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunologic Factors/therapeutic use , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Virus Internalization/drug effects , Virus Replication/drug effects
12.
Proc Natl Acad Sci U S A ; 117(34): 20803-20813, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-695945

ABSTRACT

Virus entry is a multistep process. It initiates when the virus attaches to the host cell and ends when the viral contents reach the cytosol. Genetically unrelated viruses can subvert analogous subcellular mechanisms and use similar trafficking pathways for successful entry. Antiviral strategies targeting early steps of infection are therefore appealing, particularly when the probability for successful interference through a common step is highest. We describe here potent inhibitory effects on content release and infection by chimeric vesicular stomatitis virus (VSV) containing the envelope proteins of Zaire ebolavirus (VSV-ZEBOV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (VSV-SARS-CoV-2) elicited by Apilimod and Vacuolin-1, small-molecule inhibitors of the main endosomal phosphatidylinositol-3-phosphate/phosphatidylinositol 5-kinase, PIKfyve. We also describe potent inhibition of SARS-CoV-2 strain 2019-nCoV/USA-WA1/2020 by Apilimod. These results define tools for studying the intracellular trafficking of pathogens elicited by inhibition of PIKfyve kinase and suggest the potential for targeting this kinase in developing small-molecule antivirals against SARS-CoV-2.


Subject(s)
Betacoronavirus/drug effects , Ebolavirus/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Morpholines/pharmacology , Phosphatidylinositol 3-Kinases , Triazines/pharmacology , Virus Internalization/drug effects , Animals , Betacoronavirus/physiology , Cells, Cultured , Coronavirus Infections , Ebolavirus/physiology , Gene Editing , Humans , Pandemics , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Pneumonia, Viral , Viral Envelope Proteins/genetics
13.
F1000Res ; 9: 663, 2020.
Article in English | MEDLINE | ID: covidwho-695359

ABSTRACT

Background: Human coronavirus (SARS-CoV-2) is causing a pandemic with significant morbidity and mortality. As no effective novel drugs are available currently, drug repurposing is an alternative intervention strategy. Here we present an  in silico drug repurposing study that implements successful concepts of computer-aided drug design (CADD) technology for repurposing known drugs to interfere with viral cellular entry via the spike glycoprotein (SARS-CoV-2-S), which mediates host cell entry via the hACE2 receptor. Methods: A total of 4015 known and approved small molecules were screened for interaction with SARS-CoV-2-S through docking studies and 15 lead molecules were shortlisted. Additionally, streptomycin, ciprofloxacin, and glycyrrhizic acid (GA) were selected based on their reported anti-viral activity, safety, availability and affordability. The 18 molecules were subjected to molecular dynamics (MD) simulation. Results: The MD simulation results indicate that GA of plant origin may be repurposed for SARS-CoV-2 intervention, pending further studies. Conclusions: Repurposing is a beneficial strategy for treating COVID-19 with existing drugs. It is aimed at using docking studies to screen molecules for clinical application and investigating their efficacy in inhibiting SARS-CoV-2-S. SARS-CoV-2-S is a key pathogenic protein that mediates pathogen-host interaction. Hence, the molecules screened for inhibitory properties against SARS-CoV-2-S can be clinically used to treat COVID-19 since the safety profile is already known.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections , Drug Design , Drug Repositioning , Pandemics , Pneumonia, Viral , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Humans , Molecular Docking Simulation , Peptidyl-Dipeptidase A , Virus Internalization/drug effects
14.
Acta Pharmacol Sin ; 41(9): 1141-1149, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-694139

ABSTRACT

Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus , Coronavirus Infections , Pandemics , Pneumonia, Viral , Spike Glycoprotein, Coronavirus/physiology , Virus Internalization/drug effects , Betacoronavirus/drug effects , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Discovery/methods , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology
15.
Front Immunol ; 11: 1712, 2020.
Article in English | MEDLINE | ID: covidwho-690100

ABSTRACT

During the current corona pandemic, new therapeutic options against this viral disease are urgently desired. Due to the rapid spread and immense number of affected individuals worldwide, cost-effective, globally available, and safe options with minimal side effects and simple application are extremely warranted. This review will therefore discuss the potential of zinc as preventive and therapeutic agent alone or in combination with other strategies, as zinc meets all the above described criteria. While a variety of data on the association of the individual zinc status with viral and respiratory tract infections are available, study evidence regarding COVID-19 is so far missing but can be assumed as was indicated by others and is detailed in this perspective, focusing on re-balancing of the immune response by zinc supplementation. Especially, the role of zinc in viral-induced vascular complications has barely been discussed, so far. Interestingly, most of the risk groups described for COVID-19 are at the same time groups that were associated with zinc deficiency. As zinc is essential to preserve natural tissue barriers such as the respiratory epithelium, preventing pathogen entry, for a balanced function of the immune system and the redox system, zinc deficiency can probably be added to the factors predisposing individuals to infection and detrimental progression of COVID-19. Finally, due to its direct antiviral properties, it can be assumed that zinc administration is beneficial for most of the population, especially those with suboptimal zinc status.


Subject(s)
Antiviral Agents/immunology , Betacoronavirus/physiology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Dietary Supplements , Pandemics/prevention & control , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Zinc/immunology , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Cilia/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Homeostasis/immunology , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Respiratory Mucosa/immunology , Virus Internalization/drug effects , Virus Replication/drug effects , Zinc/deficiency , Zinc/pharmacology , Zinc/therapeutic use
16.
Int J Mol Med ; 46(2): 467-488, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-678269

ABSTRACT

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pneumonia, Viral/drug therapy , Virus Internalization/drug effects , Angiotensin II Type 1 Receptor Blockers/classification , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , Bromhexine/pharmacology , Bromhexine/therapeutic use , Chlorpromazine/pharmacology , Chlorpromazine/therapeutic use , Clinical Trials as Topic/methods , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Diminazene/pharmacology , Diminazene/therapeutic use , Drug Repositioning/methods , Drug Repositioning/standards , Drug Repositioning/trends , Gabexate/analogs & derivatives , Gabexate/pharmacology , Gabexate/therapeutic use , Humans , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Peptidyl-Dipeptidase A/therapeutic use , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Receptor, Angiotensin, Type 1/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/therapeutic use , Signal Transduction/drug effects
17.
Int J Mol Sci ; 21(15)2020 Jul 23.
Article in English | MEDLINE | ID: covidwho-669635

ABSTRACT

The ongoing pandemic of coronavirus disease-2019 (COVID-19) is being caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease continues to present significant challenges to the health care systems around the world. This is primarily because of the lack of vaccines to protect against the infection and the lack of highly effective therapeutics to prevent and/or treat the illness. Nevertheless, researchers have swiftly responded to the pandemic by advancing old and new potential therapeutics into clinical trials. In this review, we summarize potential anti-COVID-19 therapeutics that block the early stage of the viral life cycle. The review presents the structures, mechanisms, and reported results of clinical trials of potential therapeutics that have been listed in clinicaltrials.gov. Given the fact that some of these therapeutics are multi-acting molecules, other relevant mechanisms will also be described. The reviewed therapeutics include small molecules and macromolecules of sulfated polysaccharides, polypeptides, and monoclonal antibodies. The potential therapeutics target viral and/or host proteins or processes that facilitate the early stage of the viral infection. Frequent targets are the viral spike protein, the host angiotensin converting enzyme 2, the host transmembrane protease serine 2, and clathrin-mediated endocytosis process. Overall, the review aims at presenting update-to-date details, so as to enhance awareness of potential therapeutics, and thus, to catalyze their appropriate use in combating the pandemic.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Clinical Trials as Topic , Humans , Pandemics , Peptides/chemistry , Peptides/pharmacology , Peptides/therapeutic use , Polysaccharides/chemistry , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Virus Attachment/drug effects , Virus Internalization/drug effects
18.
Cell Signal ; 74: 109721, 2020 10.
Article in English | MEDLINE | ID: covidwho-665126

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense, single-stranded RNA virus that causes the potentially lethal Covid-19 respiratory tract infection. It does so by binding to host cell angiotensin converting enzyme 2 (ACE2) receptors, leading to endocytosis with the receptor, and subsequently using the host cell's machinery to replicate copies of itself and invade new cells. The extent of the spread of infection in the body is dependent on the pattern of ACE2 expression and overreaction of the immune system. Additionally, by inducing an imbalance in the renin-angiotensin-aldosterone system (RAAS) and the loss of ACE2 would favour the progression of inflammatory and thrombotic processes in the lungs. No drug or vaccine has yet been approved to treat human coronaviruses. Hundreds of clinical trials on existing approved drugs from different classes acting on a multitude of targets in the virus life cycle are ongoing to examine potential effectiveness for the prevention and treatment of the infection. This review summarizes the SARS-CoV-2 virus life cycle in the host cell and provides a biological and pathological point of view for repurposed and experimental drugs for this novel coronavirus. The viral life cycle provides potential targets for drug therapy.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/metabolism , Coronavirus Infections/drug therapy , Drug Repositioning/methods , Life Cycle Stages/drug effects , Molecular Targeted Therapy/methods , Pneumonia, Viral/drug therapy , Betacoronavirus/chemistry , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Humans , Pandemics/prevention & control , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , Renin-Angiotensin System/drug effects , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Viral Vaccines/immunology , Virus Internalization/drug effects , Virus Replication/drug effects
19.
Anal Chem ; 92(16): 10930-10934, 2020 08 18.
Article in English | MEDLINE | ID: covidwho-661160

ABSTRACT

The emergence and rapid proliferation of the novel coronavirus (SARS-CoV-2) resulted in a global pandemic, with over 6,000,000 cases and nearly 400,000 deaths reported worldwide by the end of May 2020. A rush to find a cure prompted re-evaluation of a range of existing therapeutics vis-à-vis their potential role in treating COVID-19, placing a premium on analytical tools capable of supporting such efforts. Native mass spectrometry (MS) has long been a tool of choice in supporting the mechanistic studies of drug/therapeutic target interactions, but its applications remain limited in the cases that involve systems with a high level of structural heterogeneity. Both SARS-CoV-2 spike protein (S-protein), a critical element of the viral entry to the host cell, and ACE2, its docking site on the host cell surface, are extensively glycosylated, making them challenging targets for native MS. However, supplementing native MS with a gas-phase ion manipulation technique (limited charge reduction) allows meaningful information to be obtained on the noncovalent complexes formed by ACE2 and the receptor-binding domain (RBD) of the S-protein. Using this technique in combination with molecular modeling also allows the role of heparin in destabilizing the ACE2/RBD association to be studied, providing critical information for understanding the molecular mechanism of its interference with the virus docking to the host cell receptor. Both short (pentasaccharide) and relatively long (eicosasaccharide) heparin oligomers form 1:1 complexes with RBD, indicating the presence of a single binding site. This association alters the protein conformation (to maximize the contiguous patch of the positive charge on the RBD surface), resulting in a notable decrease in its ability to associate with ACE2. The destabilizing effect of heparin is more pronounced in the case of the longer chains due to the electrostatic repulsion between the low-pI ACE2 and the heparin segments not accommodated on the RBD surface. In addition to providing important mechanistic information on attenuation of the ACE2/RBD association by heparin, the study demonstrates the yet untapped potential of native MS coupled to gas-phase ion chemistry as a means of facilitating rational repurposing of the existing medicines for treating COVID-19.


Subject(s)
Coronavirus Infections/pathology , Heparin/metabolism , Mass Spectrometry/methods , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Betacoronavirus/isolation & purification , Betacoronavirus/metabolism , Binding Sites , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Gases/chemistry , Heparin/pharmacology , Heparin/therapeutic use , Humans , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Binding , Protein Domains , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
20.
Clin Appl Thromb Hemost ; 26: 1076029620936776, 2020.
Article in English | MEDLINE | ID: covidwho-657787

ABSTRACT

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/complications , Pandemics , Pneumonia, Viral/complications , Thrombophilia/etiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anticoagulants/therapeutic use , Arterial Occlusive Diseases/etiology , Arterial Occlusive Diseases/physiopathology , Arterial Occlusive Diseases/virology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Catheterization, Swan-Ganz , Combined Modality Therapy , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Fibrinolytic Agents/therapeutic use , Humans , Hyperbaric Oxygenation , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pulmonary Embolism/etiology , Pulmonary Embolism/therapy , Pulmonary Embolism/virology , Respiratory Distress Syndrome, Adult/etiology , Thrombolytic Therapy/instrumentation , Thrombolytic Therapy/methods , Thrombophilia/physiopathology , Thrombophilia/therapy , Venous Thrombosis/etiology , Venous Thrombosis/physiopathology , Venous Thrombosis/virology , Virus Internalization/drug effects
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