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2.
Molecules ; 26(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1518621

ABSTRACT

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/metabolism , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , Biological Products/metabolism , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Density Functional Theory , Humans , Ligands , Molecular Docking Simulation , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Vidarabine/chemistry , Vidarabine/metabolism , Vidarabine/therapeutic use , Viral Regulatory and Accessory Proteins/metabolism
3.
Molecules ; 26(20)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1463775

ABSTRACT

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine (SAM), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44, 48, 85, 102, 105, 182, 220, 221, 282, 284, 285, 301, and 302. The docking studies picked 48, 182, 220, 221, and 284. While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182. Finally, a density-functional theory (DFT) study suggested vidarabine (182) to be the most relevant SARS-Cov-2 nsp10 inhibitor.


Subject(s)
Antiviral Agents/chemistry , Biological Products/chemistry , SARS-CoV-2/metabolism , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , Biological Products/metabolism , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Density Functional Theory , Humans , Ligands , Molecular Docking Simulation , S-Adenosylmethionine/chemistry , S-Adenosylmethionine/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use , Vidarabine/chemistry , Vidarabine/metabolism , Vidarabine/therapeutic use , Viral Regulatory and Accessory Proteins/metabolism
4.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1348051

ABSTRACT

The identification of protein-ligand interaction plays a key role in biochemical research and drug discovery. Although deep learning has recently shown great promise in discovering new drugs, there remains a gap between deep learning-based and experimental approaches. Here, we propose a novel framework, named AIMEE, integrating AI model and enzymological experiments, to identify inhibitors against 3CL protease of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2), which has taken a significant toll on people across the globe. From a bioactive chemical library, we have conducted two rounds of experiments and identified six novel inhibitors with a hit rate of 29.41%, and four of them showed an IC50 value <3 µM. Moreover, we explored the interpretability of the central model in AIMEE, mapping the deep learning extracted features to the domain knowledge of chemical properties. Based on this knowledge, a commercially available compound was selected and was proven to be an activity-based probe of 3CLpro. This work highlights the great potential of combining deep learning models and biochemical experiments for intelligent iteration and for expanding the boundaries of drug discovery. The code and data are available at https://github.com/SIAT-code/AIMEE.


Subject(s)
COVID-19/drug therapy , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , Small Molecule Libraries/chemistry , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Artificial Intelligence , COVID-19/genetics , COVID-19/virology , Drug Discovery , Humans , Ligands , Protease Inhibitors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Small Molecule Libraries/therapeutic use
5.
Front Immunol ; 12: 658519, 2021.
Article in English | MEDLINE | ID: covidwho-1317222

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly pathogenic novel virus that has caused a massive pandemic called coronavirus disease 2019 (COVID-19) worldwide. Wuhan, a city in China became the epicenter of the outbreak of COVID-19 in December 2019. The disease was declared a pandemic globally by the World Health Organization (WHO) on 11 March 2020. SARS-CoV-2 is a beta CoV of the Coronaviridae family which usually causes respiratory symptoms that resemble common cold. Multiple countries have experienced multiple waves of the disease and scientific experts are consistently working to find answers to several unresolved questions, with the aim to find the most suitable ways to contain the virus. Furthermore, potential therapeutic strategies and vaccine development for COVID-19 management are also considered. Currently, substantial efforts have been made to develop successful and safe treatments and SARS-CoV-2 vaccines. Some vaccines, such as inactivated vaccines, nucleic acid-based, and vector-based vaccines, have entered phase 3 clinical trials. Additionally, diverse small molecule drugs, peptides and antibodies are being developed to treat COVID-19. We present here an overview of the virus interaction with the host and environment and anti-CoV therapeutic strategies; including vaccines and other methodologies, designed for prophylaxis and treatment of SARS-CoV-2 infection with the hope that this integrative analysis could help develop novel therapeutic approaches against COVID-19.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/epidemiology , COVID-19/prevention & control , Pandemics/prevention & control , SARS-CoV-2/immunology , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , COVID-19 Vaccines/immunology , Host Microbial Interactions/immunology , Humans , Immunity , Mutation Rate , SARS-CoV-2/genetics , Small Molecule Libraries/therapeutic use , Vaccines, DNA/immunology , Vaccines, DNA/therapeutic use , Vaccines, Inactivated/immunology , Vaccines, Inactivated/therapeutic use
6.
Mol Omics ; 17(3): 376-393, 2021 06 14.
Article in English | MEDLINE | ID: covidwho-1281750

ABSTRACT

Metabolomics has emerged as an invaluable tool that can be used along with genomics, transcriptomics and proteomics to understand host-pathogen interactions at small-molecule levels. Metabolomics has been used to study a variety of infectious diseases and applications. The most common application of metabolomics is for prognostic and diagnostic purposes, specifically the screening of disease-specific biomarkers by either NMR-based or mass spectrometry-based metabolomics. In addition, metabolomics is of great significance for the discovery of druggable metabolic enzymes and/or metabolic regulators through the use of state-of-the-art flux analysis, for example, via the elucidation of metabolic mechanisms. This review discusses the application of metabolomics technologies to biomarker screening, the discovery of drug targets in infectious diseases such as viral, bacterial and parasite infections and immunometabolomics, highlights the challenges associated with accessing metabolite compartmentalization and discusses the available tools for determining local metabolite concentrations.


Subject(s)
Biomarkers/metabolism , Communicable Diseases/metabolism , Metabolomics/methods , Communicable Diseases/drug therapy , Drug Discovery , Humans , Metabolic Networks and Pathways/drug effects , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use
7.
SLAS Discov ; 26(8): 974-983, 2021 09.
Article in English | MEDLINE | ID: covidwho-1277904

ABSTRACT

Affinity selection mass spectrometry (ASMS) has emerged as a powerful high-throughput screening tool used in drug discovery to identify novel ligands against therapeutic targets. This report describes the first high-throughput screen using a novel self-assembled monolayer desorption ionization (SAMDI)-ASMS methodology to reveal ligands for the human rhinovirus 3C (HRV3C) protease. The approach combines self-assembled monolayers of alkanethiolates on gold with matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry (MS), a technique termed SAMDI-ASMS. The primary screen of more than 100,000 compounds in pools of 8 compounds per well was completed in less than 8 h, and informs on the binding potential and selectivity of each compound. Initial hits were confirmed in follow-up SAMDI-ASMS experiments in single-concentration and dose-response curves. The ligands identified by SAMDI-ASMS were further validated using differential scanning fluorimetry (DSF) and in functional protease assays against HRV3C and the related SARS-CoV-2 3CLpro enzyme. SAMDI-ASMS offers key benefits for drug discovery over traditional ASMS approaches, including the high-throughput workflow and readout, minimizing compound misbehavior by using smaller compound pools, and up to a 50-fold reduction in reagent consumption. The flexibility of this novel technology opens avenues for high-throughput ASMS assays of any target, thereby accelerating drug discovery for diverse diseases.


Subject(s)
COVID-19/drug therapy , High-Throughput Screening Assays , Rhinovirus/drug effects , Small Molecule Libraries/chemistry , 3C Viral Proteases/chemistry , COVID-19/virology , Drug Discovery , Humans , Ligands , Mass Spectrometry , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Small Molecule Libraries/isolation & purification , Small Molecule Libraries/therapeutic use
8.
Int J Mol Sci ; 22(12)2021 Jun 16.
Article in English | MEDLINE | ID: covidwho-1273456

ABSTRACT

Although the approved vaccines are proving to be of utmost importance in containing the Coronavirus disease 2019 (COVID-19) threat, they will hardly be resolutive as new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, a single-stranded RNA virus) variants might be insensitive to the immune response they induce. In this scenario, developing an effective therapy is still a dire need. Different targets for therapeutic antibodies and diagnostics have been identified, among which the SARS-CoV-2 spike (S) glycoprotein, particularly its receptor-binding domain, has been defined as crucial. In this context, we aim to focus attention also on the role played by the S N-terminal domain (S1-NTD) in the virus attachment, already recognized as a valuable target for neutralizing antibodies, in particular, building on a cavity mapping indicating the presence of two druggable pockets and on the recent literature hypothesizing the presence of a ganglioside-binding domain. In this perspective, we aim at proposing S1-NTD as a putative target for designing small molecules hopefully able to hamper the SARS-CoV-2 attachment to host cells.


Subject(s)
SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Binding Sites , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , Drug Repositioning , Humans , Molecular Dynamics Simulation , N-Acetylneuraminic Acid/analogs & derivatives , N-Acetylneuraminic Acid/metabolism , N-Acetylneuraminic Acid/pharmacology , N-Acetylneuraminic Acid/therapeutic use , Protein Binding , Protein Domains , SARS-CoV-2/isolation & purification , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Spike Glycoprotein, Coronavirus/chemistry , Virus Attachment/drug effects
9.
Int J Mol Sci ; 22(4)2021 Feb 11.
Article in English | MEDLINE | ID: covidwho-1079663

ABSTRACT

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Discovery , Lysosomes/drug effects , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Chlorpromazine/pharmacokinetics , Chlorpromazine/pharmacology , Chlorpromazine/therapeutic use , Cytokine Release Syndrome/drug therapy , Drug Discovery/methods , Drug Repositioning/methods , Fluvoxamine/pharmacokinetics , Fluvoxamine/pharmacology , Fluvoxamine/therapeutic use , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Interleukin-1/antagonists & inhibitors , Interleukin-1/immunology , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Lung/drug effects , Lung/immunology , Lung/metabolism , Lung/virology , Lysosomes/immunology , Lysosomes/metabolism , Lysosomes/virology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Small Molecule Libraries/pharmacokinetics , Small Molecule Libraries/therapeutic use , Virus Replication/drug effects
10.
Bioorg Med Chem ; 33: 116040, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1064895

ABSTRACT

The COVID-19 pandemic continues without specific treatment. In this study it is proposed compounds that can be developed as adjuvant / complementary drugs against COVID-19. Through a search for molecular docking, for the development of a new drug using pharmacological compounds targeting the b1 region in neuropilin-1 (NRP1), which is important for the interaction with the S1 region of the S-Protein of SARS-CoV-2, to slow down the infection process of this virus. A molecular docking was performed using almost 500,000 compounds targeted to interact in the region between amino acids (Thr316, Asp320, Ser346, Thr349, and Tyr353) in NRP1 to determine compounds able to hinder the interaction with the S1 region in the S-Protein. In this study, ten compounds are proposed as potential inhibitors between S1 region in the S-Protein of SARS-CoV-2 with the b1 region in NRP1, to develop a new adjuvant / complementary drug against COVID-19, and to hinder the interaction between SARS-CoV-2 and human cells, with a high probability to be safe in humans, validated by web servers for prediction of ADME and toxicity (PreADMET).


Subject(s)
Molecular Docking Simulation , Neuropilin-1/antagonists & inhibitors , Small Molecule Libraries/chemistry , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Drug Repositioning , Humans , Neuropilin-1/metabolism , SARS-CoV-2/isolation & purification , Small Molecule Libraries/metabolism , Small Molecule Libraries/therapeutic use
12.
Med Res Rev ; 41(3): 1375-1426, 2021 05.
Article in English | MEDLINE | ID: covidwho-956732

ABSTRACT

In the past two decades, three highly pathogenic human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus, and, recently, SARS-CoV-2, have caused pandemics of severe acute respiratory diseases with alarming morbidity and mortality. Due to the lack of specific anti-CoV therapies, the ongoing pandemic of coronavirus disease 2019 (COVID-19) poses a great challenge to clinical management and highlights an urgent need for effective interventions. Drug repurposing is a rapid and feasible strategy to identify effective drugs for combating this deadly infection. In this review, we summarize the therapeutic CoV targets, focus on the existing small molecule drugs that have the potential to be repurposed for existing and emerging CoV infections of the future, and discuss the clinical progress of developing small molecule drugs for COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Antiviral Agents/pharmacology , COVID-19/virology , Drug Delivery Systems , Humans , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use
13.
Biomolecules ; 10(11)2020 11 06.
Article in English | MEDLINE | ID: covidwho-918176

ABSTRACT

Natural products and semi-synthetic compounds continue to be a significant source of drug candidates for a broad range of diseases, including coronavirus disease 2019 (COVID-19), which is causing the current pandemic. Besides being attractive sources of bioactive compounds for further development or optimization, natural products are excellent substrates of unique substructures for fragment-based drug discovery. To this end, fragment libraries should be incorporated into automated drug design pipelines. However, public fragment libraries based on extensive collections of natural products are still limited. Herein, we report the generation and analysis of a fragment library of natural products derived from a database with more than 400,000 compounds. We also report fragment libraries of a large food chemical database and other compound datasets of interest in drug discovery, including compound libraries relevant for COVID-19 drug discovery. The fragment libraries were characterized in terms of content and diversity.


Subject(s)
Biological Products/chemistry , Drug Discovery , Algorithms , Betacoronavirus/isolation & purification , Biological Products/therapeutic use , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Databases, Chemical , Humans , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Small Molecule Libraries/chemistry , Small Molecule Libraries/therapeutic use
14.
Mol Divers ; 25(3): 1717-1730, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-808448

ABSTRACT

Recently, various computational methods have been proposed to find new therapeutic applications of the existing drugs. The Multimodal Restricted Boltzmann Machine approach (MM-RBM), which has the capability to connect the information about the multiple modalities, can be applied to the problem of drug repurposing. The present study utilized MM-RBM to combine two types of data, including the chemical structures data of small molecules and differentially expressed genes as well as small molecules perturbations. In the proposed method, two separate RBMs were applied to find out the features and the specific probability distribution of each datum (modality). Besides, RBM was used to integrate the discovered features, resulting in the identification of the probability distribution of the combined data. The results demonstrated the significance of the clusters acquired by our model. These clusters were used to discover the medicines which were remarkably similar to the proposed medications to treat COVID-19. Moreover, the chemical structures of some small molecules as well as dysregulated genes' effect led us to suggest using these molecules to treat COVID-19. The results also showed that the proposed method might prove useful in detecting the highly promising remedies for COVID-19 with minimum side effects. All the source codes are accessible using https://github.com/LBBSoft/Multimodal-Drug-Repurposing.git.


Subject(s)
COVID-19/drug therapy , Deep Learning , Drug Repositioning/methods , Probability , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use
15.
J Med Chem ; 63(22): 13205-13227, 2020 11 25.
Article in English | MEDLINE | ID: covidwho-741659

ABSTRACT

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 20 million people infected worldwide with an average mortality rate of 3.6%. This virus poses major challenges to public health, as it not only is highly contagious but also can be transmitted by asymptomatic infected individuals. COVID-19 is clinically difficult to manage due to a lack of specific antiviral drugs or vaccines. In this article, Chinese therapy strategies for treating COVID-19 patients, including current applications of traditional Chinese medicine (TCM), are comprehensively reviewed. Furthermore, 72 small molecules from natural products and TCM with reported antiviral activity against human coronaviruses (CoVs) are identified from published literature, and their potential applications in combating SARS-CoV-2 are discussed. Among these, the clinical efficacies of some accessible drugs such as remdesivir (RDV) and favipiravir (FPV) for COVID-19 are emphatically summarized. We hope this review provides a foundation for managing the worsening pandemic and developing antivirals against SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus Protease Inhibitors/therapeutic use , Drugs, Chinese Herbal/therapeutic use , SARS-CoV-2/drug effects , Small Molecule Libraries/therapeutic use , COVID-19/epidemiology , China/epidemiology , Humans , Medicine, Chinese Traditional , SARS-CoV-2/enzymology
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 , COVID-19 , Clinical Trials as Topic , Humans , Pandemics , Peptides/chemistry , Peptides/pharmacology , Peptides/therapeutic use , Polysaccharides/chemistry , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , SARS-CoV-2 , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Virus Attachment/drug effects , Virus Internalization/drug effects
18.
Int J Mol Sci ; 21(13)2020 Jun 30.
Article in English | MEDLINE | ID: covidwho-635823

ABSTRACT

Vimentin is an intermediate filament protein that plays key roles in integration of cytoskeletal functions, and therefore in basic cellular processes such as cell division and migration. Consequently, vimentin has complex implications in pathophysiology. Vimentin is required for a proper immune response, but it can also act as an autoantigen in autoimmune diseases or as a damage signal. Although vimentin is a predominantly cytoplasmic protein, it can also appear at extracellular locations, either in a secreted form or at the surface of numerous cell types, often in relation to cell activation, inflammation, injury or senescence. Cell surface targeting of vimentin appears to associate with the occurrence of certain posttranslational modifications, such as phosphorylation and/or oxidative damage. At the cell surface, vimentin can act as a receptor for bacterial and viral pathogens. Indeed, vimentin has been shown to play important roles in virus attachment and entry of severe acute respiratory syndrome-related coronavirus (SARS-CoV), dengue and encephalitis viruses, among others. Moreover, the presence of vimentin in specific virus-targeted cells and its induction by proinflammatory cytokines and tissue damage contribute to its implication in viral infection. Here, we recapitulate some of the pathophysiological implications of vimentin, including the involvement of cell surface vimentin in interaction with pathogens, with a special focus on its role as a cellular receptor or co-receptor for viruses. In addition, we provide a perspective on approaches to target vimentin, including antibodies or chemical agents that could modulate these interactions to potentially interfere with viral pathogenesis, which could be useful when multi-target antiviral strategies are needed.


Subject(s)
SARS Virus/physiology , Vimentin/metabolism , Virus Diseases/pathology , Antibodies/immunology , Antibodies/metabolism , Antibodies/therapeutic use , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/drug therapy , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Vimentin/chemistry , Vimentin/immunology , Virus Diseases/drug therapy , Virus Diseases/metabolism , Virus Replication/drug effects
19.
Biochem Biophys Res Commun ; 528(1): 35-38, 2020 07 12.
Article in English | MEDLINE | ID: covidwho-388951

ABSTRACT

The recent release of COVID-19 spike glycoprotein allows detailed analysis of the structural features that are required for stabilizing the infective form of its quaternary assembly. Trying to disassemble the trimeric structure of COVID-19 spike glycoprotein, we analyzed single protomer surfaces searching for concave moieties that are located at the three protomer-protomer interfaces. The presence of some druggable pockets at these interfaces suggested that some of the available drugs in Drug Bank could destabilize the quaternary spike glycoprotein formation by binding to these pockets, therefore interfering with COVID-19 life cycle. The approach we propose here can be an additional strategy to fight against the deadly virus. Ligands of COVID-19 spike glycoprotein that we have predicted in the present computational investigation, might be the basis for new experimental studies in vitro and in vivo.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Evaluation, Preclinical , Pneumonia, Viral/drug therapy , Protein Multimerization/drug effects , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Sequence , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/chemistry , Betacoronavirus/physiology , Binding Sites , COVID-19 , Coronavirus Infections/epidemiology , Ligands , Models, Molecular , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Small Molecule Libraries/chemistry , Small Molecule Libraries/therapeutic use
20.
Acta Biomed ; 91(1): 161-164, 2020 03 19.
Article in English | MEDLINE | ID: covidwho-10519

ABSTRACT

BACKGROUND: Viral infectivity depends on interactions between components of the host cell plasma membrane and the virus envelope. Here we review strategies that could help stem the advance of the SARS-COV-2 epidemic. METHODS AND RESULTS: We focus on the role of lipid structures, such as lipid rafts and cholesterol, involved in the process, mediated by endocytosis, by which viruses attach to and infect cells. Previous studies have shown that many naturally derived substances, such as cyclodextrin and sterols, could reduce the infectivity of many types of viruses, including the coronavirus family, through interference with lipid-dependent attachment to human host cells. CONCLUSIONS: Certain molecules prove able to reduce the infectivity of some coronaviruses, possibly by inhibiting viral lipid-dependent attachment to host cells. More research into these molecules and methods would be worthwhile as it could provide insights the mechanism of transmission of SARS-COV-2 and, into how they could become a basis for new antiviral strategies.


Subject(s)
Antiviral Agents , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Small Molecule Libraries , Virus Attachment/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/physiology , COVID-19 , Humans , Lipids , SARS-CoV-2 , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use
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