Targeting SARS-CoV-2 using polycomb inhibitors as antiviral agents.
Ontology highlight
ABSTRACT:
SUBMITTER: Ayaz S
PROVIDER: S-EPMC7491010 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Publications
Targeting SARS-CoV-2 using polycomb inhibitors as antiviral agents.
Ayaz Sameer S Crea Francesco F
Epigenomics 20200501 10
Similar Datasets
Project description:We synthesized a set of small molecules using a molecular hybridization approach with good yields. The antiviral properties of the synthesized conjugates against the SAR-CoV-2 virus were investigated and their cytotoxicity was also determined. Among all the synthesized conjugates, compound 9f showed potential against SARS-CoV-2 and low cytotoxicity. The conjugates' selectivity indexes (SIs) were determined to correlate the antiviral properties and cytotoxicity. The observed biological data were further validated using computational studies.
| S-EPMC9501548 | biostudies-literature
Project description:SARS-CoV-2, the cause of the currently ongoing COVID-19 pandemic, encodes its own mRNA capping machinery. Insights into this capping system may provide new ideas for therapeutic interventions and drug discovery. In this work, we employ a previously developed Py-FLINT screening approach to study the inhibitory effects of compounds against the cap guanine N7-methyltransferase enzyme, which is involved in SARS-CoV-2 mRNA capping. We screened five commercially available libraries (7039 compounds in total) to identify 83 inhibitors with IC50 < 50 μM, which were further validated using RP HPLC and dot blot assays. Novel fluorescence anisotropy binding assays were developed to examine the targeted binding site. The inhibitor structures were analyzed for structure-activity relationships in order to define common structural patterns. Finally, the most potent inhibitors were tested for antiviral activity on SARS-CoV-2 in a cell based assay.
| S-EPMC8299157 | biostudies-literature
Project description:The severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2), the infectious agent responsible for COVID-19 - has caused more than 2.5 million deaths worldwide and triggered a global pandemic. Even with successful vaccines being delivered, there is an urgent need for novel treatments to combat SARS-CoV-2, and other emerging viral diseases. While several organic small molecule drug candidates are in development, some effort has also been devoted towards the application of metal complexes as potential antiviral agents against SARS-CoV-2. Herein, the metal complexes that have been reported to show antiviral activity against SARS-CoV-2 or one of its target proteins are described and their proposed mechanisms of action are discussed.
| S-EPMC8239769 | biostudies-literature
Project description:New variations of SARS-CoV-2 continue to emerge in the global pandemic, which may be resistant to at least some vaccines in COVID-19, indicating that drug and vaccine development must be continuously strengthened. NSP10 plays an essential role in SARS-CoV-2 viral life cycle. It stimulates the enzymatic activities of NSP14-ExoN and NSP16-O-MTase by the formation of NSP10/NSP14 and NSP10/NSP16 complexes. Inhibiting NSP10 can block the binding of NSP10 to NSP14 and NSP16. This study has identified potential natural NSP10 inhibitors from ZINC database. The protein druggable pocket was identified for screening candidates. Molecular docking of the selected compounds was performed and MM-GBSA binding energy was calculated. After ADMET assessment, 4 hits were obtained for favorable druggability. The analysis of site interactions suggested that the hits all had excellent binding. Molecular dynamics studies revealed that selected natural compounds stably bind to NSP10. These compounds were identified as potential leads against NSP10 for the development of strategies to combat SARS-CoV-2 replication and could serve as the basis for further studies.
| S-EPMC9376029 | biostudies-literature
Project description:Despite the intense development of vaccines and antiviral therapeutics, no specific treatment of coronavirus disease 2019 (COVID-19), caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently available. Recently, X-ray crystallographic structures of a validated pharmacological target of SARS-CoV-2, the main protease (Mpro also called 3CLpro) in complex with peptide-like irreversible inhibitors have been published. We have carried out computer-aided structure-based design and optimization of peptidomimetic irreversible α-ketoamide Mpro inhibitors and their analogues using MM, MD and QM/MM methodology, with the goal to propose lead compounds with improved binding affinity to SARS-CoV-2 Mpro, enhanced specificity for pathogenic coronaviruses, decreased peptidic character, and favourable drug-like properties. The best inhibitor candidates designed in this work show largely improved interaction energies towards the Mpro and enhanced specificity due to 6 additional hydrogen bonds to the active site residues. The presented results on new SARS-CoV-2 Mpro inhibitors are expected to stimulate further research towards the development of specific anti-COVID-19 drugs.
| S-EPMC9057467 | biostudies-literature
Project description:BackgroundThe coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection became an international pandemic and created a public health crisis. The binding of the viral Spike glycoprotein to the human cell receptor angiotensin-converting enzyme 2 (ACE2) initiates viral infection. The development of efficient treatments to combat coronavirus disease is considered essential.MethodsAn in silico approach was employed to design amino acid peptide inhibitor against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The designed inhibitor (SARS-CoV-2 PEP 49) consists of amino acids with the α1 helix and the β4 - β5 sheets of ACE2. The PEP-FOLD3 web tool was used to create the 3D structures of the peptide amino acids. Analyzing the interaction between ACE2 and the RBD of the Spike protein for three protein data bank entries (6M0J, 7C8D, and 7A95) indicated that the interacting amino acids were contained inside two regions of ACE2: the α1 helical protease domain (PD) and the β4 - β5 sheets.ResultsMolecular docking analysis of the designed inhibitor demonstrated that SARS-CoV-2 PEP 49 attaches directly to the ACE2 binding site of the Spike protein with a binding affinity greater than the ACE2, implying that the SARS-CoV-2 PEP 49 model may be useful as a potential RBD binding blocker.
| S-EPMC9716172 | biostudies-literature
Project description:The emergence of severe acute respiratory syndrome (SARS-CoV-2) in 2019 marked the third occurrence of a highly pathogenic coronavirus in the human population since 2003. As the death toll surpasses 5 million globally and economic losses continue, designing drugs that could curtail infection and disease progression is critical. In the US, three highly effective Food and Drug Administration (FDA)-authorized vaccines are currently available, and Remdesivir is approved for the treatment of hospitalized patients. However, moderate vaccination rates and the sustained evolution of new viral variants necessitate the ongoing search for new antivirals. Several viral proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them the papain-like protease (PLpro) and the main protease (Mpro). Inhibition of these proteases would target viral replication, viral maturation, and suppression of host innate immune responses. Knowledge of inhibitors and assays for viruses were quickly adopted for SARS-CoV-2 protease research. Potential candidates have been identified to show inhibitory effects against PLpro and Mpro, both in biochemical assays and viral replication in cells. These results encourage further optimizations to improve prophylactic and therapeutic efficacy. In this review, we examine the latest developments of potential small-molecule inhibitors and peptide inhibitors for PLpro and Mpro, and how structural biology greatly facilitates this process.
| S-EPMC8850931 | biostudies-literature
Project description:The recent pandemic of COVID-19 has raised global health concerns. Preventing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) activity in the body is a very promising method to overcome the COVID-19 pandemic. One of the prevention methods is constraining the binding process among the human cell receptor-ACE2 and coronavirus spike protein. In the research done, the effect of deformation of the spike protein structure, due to the covalent organic frameworks (COFs), in reducing the interactions of ACE2 and the spike protein by the computational method was investigated. In this regard, atomic analysis of the interactions of ACE2 and the spike protein is provided using a molecular dynamics simulation. First, we investigated the interactions of the three different COFs, including COF-78, DAAQ-TFP, and COF-OEt, with the spike protein by analyzing the bond energies, as well as structural changes of the spike protein. Then, intermolecular interactions of the deformed spike protein along with ACE2 were assessed to clarify the protein's fusion after the deformation. As indicated by the results, although all introduced COFs deformed the spike protein in an effective way, COF-78 showed the best performance in the prevention of spike protein-ACE2 interactions by changing the molecular structure of the protein. Indeed, the interaction analysis of the deformed spike protein by COF-78 with the ACE2 showed that their interactions had the lowest absolute value of energy, along with the least amount of hydrogen bonds, in which the compaction of the protein was lower compared to the other deformed proteins. Moreover, having a high contact area with an aqueous media as well as severe fluctuations during the simulation time confirmed the positive performance of COF-78. In the current study, we aimed to introduce novel materials and COVID-19 prevention methodology that can be used in face masks and for surface disinfection.
| S-EPMC8550915 | biostudies-literature
Project description:The COVID-19 pandemic has claimed more than a million lives worldwide within a short time span. Due to the unavailability of specific antiviral drugs or vaccine, the infections are causing panic both in general public and among healthcare providers. Therefore, an urgent discovery and development of effective antiviral drug for the treatment of COVID-19 is highly desired. Targeting the main protease (Mpro) of the causative agent, SARS-CoV-2 has great potential for drug discovery and drug repurposing efforts. Published crystal structures of SARS-CoV-2 Mpro further facilitated in silico investigations for discovering new inhibitors against Mpro. The present study aimed to screen several libraries of synthetic flavonoids and benzisothiazolinones as potential SARS-CoV-2 Mpro inhibitors using in silico methods. The short-listed compounds after virtual screening were filtered through SwissADME modeling tool to remove molecules with unfavorable pharmacokinetics and medicinal properties. The drug-like molecules were further subjected to iterative docking for the identification of top binders of SARS-CoV-2 Mpro. Finally, molecular dynamic (MD) simulations and binding free energy calculations were performed for the evaluation of the dynamic behavior, stability of protein-ligand complex, and binding affinity, resulting in the identification of thioflavonol, TF-9 as a potential inhibitor of Mpro. The computational studies further revealed the binding of TF-9 close to catalytic dyad and interactions with conserved residues in the S1 subsite of the substrate binding site. Our in-silico study demonstrated that synthetic analogs of flavonoids, particularly thioflavonols, have a strong tendency to inhibit the main protease Mpro, and thereby inhibit the reproduction of SARS-CoV-2. Communicated by Ramaswamy H. Sarma.
| S-EPMC7754928 | biostudies-literature
Project description:Several reports have indicated that SARS-CoV-2 infection displays unexpected mild clinical manifestations in people with cystic fibrosis (pwCF), suggesting that CFTR expression and function may be involved in the SARS-CoV-2 life cycle. To evaluate the possible association of CFTR activity with SARS-CoV-2 replication, we tested the antiviral activity of two well-known CFTR inhibitors (IOWH-032 and PPQ-102) in wild type (WT)-CFTR bronchial cells. SARS-CoV-2 replication was inhibited by IOWH-032 treatment, with an IC50 of 4.52 μM, and by PPQ-102, with an IC50 of 15.92 μM. We confirmed this antiviral effect on primary cells (MucilAirTM wt-CFTR) using 10 μM IOWH-032. According to our results, CFTR inhibition can effectively tackle SARS-CoV-2 infection, suggesting that CFTR expression and function might play an important role in SARS-CoV-2 replication, revealing new perspectives on the mechanisms governing SARS-CoV-2 infection in both normal and CF individuals, as well as leading to potential novel treatments.
| S-EPMC10000629 | biostudies-literature