Pharmacotherapy for SARS-CoV-2 and Seizures for drug repurposing presumed on Mechanistic Targets

2021 ◽  
Vol 14 ◽  
Author(s):  
Divya Goel ◽  
Ankit Srivastava ◽  
Ángel Aledo-Serrano ◽  
Anuja Krishnan ◽  
Divya Vohora
Keyword(s):  
Valproic Acid ◽  
Viral Genome ◽  
Drug Targeting ◽  
Literature Search ◽  
Genome Structure ◽  
Drug Repurposing ◽  
Drug Candidate ◽  
Atypical Pneumonia ◽  
Comparative Toxicogenomics Database ◽  
Indirect Association

Background: The currently circulating novel SARS-CoV-2 coronavirus disease (COVID-19) has brought the whole world to a standstill. Recent studies have deciphered the viral genome structure, epidemiology and are in the process of unveiling multiple mechanisms of pathogenesis. Apart from atypical pneumonia and lung disease manifestations, this disease has also been found to be associated with neurological symptoms, which include dizziness, headache, stroke, or seizures, among others. However, a possible direct or indirect association between SARS-CoV-2 and seizures is still not clear. In any manner, it may be of interest to analyze the drugs being used for viral infection in the background of epilepsy or vice versa. Objective: To identify the most credible drug candidate for COVID-19 in persons with epilepsy or COVID-19 patients experiencing seizures. Methods: A literature search for original and review articles was performed, and further, the Comparative Toxicogenomics Database was used to unearth the most credible drug candidate. Results: Our search based on common mechanistic targets affecting SARS-CoV-2 and seizures revealed ivermectin, dexamethasone, anakinra, and tocilizumab for protection against both COVID-19 and seizures. Amongst the antiseizure medications, we found valproic acid as the most probable pharmacotherapy for COVID-19 patients experiencing seizures. Conclusion: These findings would hopefully provide the basis for initiating further studies on the pathogenesis and drug targeting strategies for this emerging infection accompanied with seizures or in people with epilepsy.

scholarly journals SARS-CoV-2: from its discovery to genome structure, transcription, and replication

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ayslan Castro Brant ◽  
Wei Tian ◽  
Vladimir Majerciak ◽  
Wei Yang ◽  
Zhi-Ming Zheng
Keyword(s):  
Viral Genome ◽  
Genome Structure ◽  
Membrane Vesicles ◽  
Regulatory Sequence ◽  
Atypical Pneumonia ◽  
Genome Replication ◽  
Long Distance ◽  
Viral Genome Replication ◽  
Infected Cells ◽  
Rna Interaction

AbstractSARS-CoV-2 is an extremely contagious respiratory virus causing adult atypical pneumonia COVID-19 with severe acute respiratory syndrome (SARS). SARS-CoV-2 has a single-stranded, positive-sense RNA (+RNA) genome of ~ 29.9 kb and exhibits significant genetic shift from different isolates. After entering the susceptible cells expressing both ACE2 and TMPRSS2, the SARS-CoV-2 genome directly functions as an mRNA to translate two polyproteins from the ORF1a and ORF1b region, which are cleaved by two viral proteases into sixteen non-structural proteins (nsp1-16) to initiate viral genome replication and transcription. The SARS-CoV-2 genome also encodes four structural (S, E, M and N) and up to six accessory (3a, 6, 7a, 7b, 8, and 9b) proteins, but their translation requires newly synthesized individual subgenomic RNAs (sgRNA) in the infected cells. Synthesis of the full-length viral genomic RNA (gRNA) and sgRNAs are conducted inside double-membrane vesicles (DMVs) by the viral replication and transcription complex (RTC), which comprises nsp7, nsp8, nsp9, nsp12, nsp13 and a short RNA primer. To produce sgRNAs, RTC starts RNA synthesis from the highly structured gRNA 3' end and switches template at various transcription regulatory sequence (TRSB) sites along the gRNA body probably mediated by a long-distance RNA–RNA interaction. The TRS motif in the gRNA 5' leader (TRSL) is responsible for the RNA–RNA interaction with the TRSB upstream of each ORF and skipping of the viral genome in between them to produce individual sgRNAs. Abundance of individual sgRNAs and viral gRNA synthesized in the infected cells depend on the location and read-through efficiency of each TRSB. Although more studies are needed, the unprecedented COVID-19 pandemic has taught the world a painful lesson that is to invest and proactively prepare future emergence of other types of coronaviruses and any other possible biological horrors.

scholarly journals The Relevance of Bioinformatics Applications in the Discovery of Vaccine Candidates and Potential Drugs for COVID-19 Treatment

2021 ◽  
Vol 15 ◽  
pp. 117793222110021
Author(s):  
Onyeka S Chukwudozie ◽  
Vincent C Duru ◽  
Charlotte C Ndiribe ◽  
Abdullahi T Aborode ◽  
Victor O Oyebanji ◽  
...  
Keyword(s):  
Viral Genome ◽  
Drug Repurposing ◽  
Protein Docking ◽  
Vaccine Research ◽  
Vaccine Candidates ◽  
Genome Data ◽  
Disease Agent ◽  
Time Critical ◽  
Antigen Antibody ◽  
Antigenic Epitopes

The application of bioinformatics to vaccine research and drug discovery has never been so essential in the fight against infectious diseases. The greatest combat of the 21st century against a debilitating disease agent SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus discovered in Wuhan, China, December 2019, has piqued an unprecedented usage of bioinformatics tools in deciphering the molecular characterizations of infectious pathogens. With the viral genome data of SARS-COV-2 been made available barely weeks after the reported outbreak, bioinformatics platforms have become an all-time critical tool to gain time in the fight against the disease pandemic. Before the outbreak, different platforms have been developed to explore antigenic epitopes, predict peptide-protein docking and antibody structures, and simulate antigen-antibody reactions and lots more. However, the advent of the pandemic witnessed an upsurge in the application of these pipelines with the development of newer ones such as the Coronavirus Explorer in the development of efficacious vaccines, drug repurposing, and/or discovery. In this review, we have explored the various pipelines available for use, their relevance, and limitations in the timely development of useful therapeutic candidates from genomic data knowledge to clinical therapy.

Viral Genome Structure

1985 ◽  
pp. 57-81 ◽  
Author(s):  
Robert H. Symons
Keyword(s):  
Viral Genome ◽  
Genome Structure

scholarly journals Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins

2020 ◽  
Author(s):  
Meenakshisundaram Balasubramaniam ◽  
Robert Shmookler Reis
Keyword(s):  
Small Molecules ◽  
Drug Targeting ◽  
Viral Infections ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Hiv Treatment ◽  
Investigational Drug ◽  
Docking Simulations ◽  
Investigational Drugs ◽  
Low Toxicity

Coronavirus disease 19 (COVID-19) is a severe acute respiratory syndrome caused by SARS-CoV-2 (2019-nCoV). While no drugs have yet been approved to treat this disease, small molecules effective against other viral infections are under clinical evaluation for therapeutic abatement of SARS-CoV-2 infections. Ongoing clinical trials include Kaletra (a combination of two protease inhibitors approved for HIV treatment), remdesivir (an investigational drug targeting RNA-dependent RNA polymerase [RdRP] of SARS-CoV-2), and hydroxychloroquine (an approved anti-malarial and immuno-modulatory drug). Since SARS-CoV-2 replication depends on three virally encoded proteins (RdRP, papain-like proteinase, and helicase), we screened 54 FDA-approved antiviral drugs and ~3300 investigational drugs for binding to these proteins using targeted and unbiased docking simulations and computational modeling. Elbasvir, a drug approved for treating hepatitis C, is predicted to bind stably and preferentially to all three proteins. At the therapeutic dosage, elbasvir has low toxicity (liver enzymes transiently elevated in 1% of subjects) and well-characterized drug-drug interactions. We predict that treatment with elbasvir, alone or in combination with other drugs such as grazoprevir, could efficiently block SARS-CoV-2 replication. The concerted action of elbasvir on at least three targets essential for viral replication renders viral mutation to drug resistance extremely unlikely.

scholarly journals Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

2021 ◽  
Vol 12 ◽  
Author(s):  
Charlotte Kern ◽  
Verena Schöning ◽  
Carlos Chaccour ◽  
Felix Hammann
Keyword(s):  
Drug Repurposing ◽  
Antiviral Effect ◽  
Drug Candidate ◽  
Appreciable Effect ◽  
Viral Kinetics ◽  
Future Drug ◽  
Dosing Regimens ◽  
Clinical Trial Results

Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3–0.6 log units and exposure by 8.8–22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

scholarly journals Drug repurposing: Hydroxyurea therapy improves the transfusion-free interval in HbE/beta-thalassemia–major patients with Xmn1 polymorphism

2021 ◽  
Author(s):  
Debojoyti Ghosh ◽  
Amrita Panja ◽  
Dipankar Saha ◽  
Uma Banerjee ◽  
Asok Kumar Dutta ◽  
...  
Keyword(s):  
High Performance ◽  
Complete Blood Count ◽  
Drug Repurposing ◽  
Fetal Hemoglobin ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Drug Candidate ◽  
Free Interval ◽  
Pcr Rflp ◽  
Hydroxyurea Therapy

AbstractAimsHbE/β-thalassemia is the prevalent form of severe β-thalassemia in Asian countries. Hydroxyurea (HU) is the most common drug used for the management of sickle-cell anemia but not thalassemia. Here, we aimed to assess clinical HU response among patients with HbE/β-thalassemia with respect to Xmn1 γGglobin polymorphism and elucidate the association between this polymorphism and HU response efficacy.MethodsWe enrolled 49 transfusion-dependent patients with HbE/β-thalassemia. Fetal hemoglobin level was measured using High-performance liquid chromatography (HPLC) and complete blood count was determined pre- and post-HU therapy. Polymerase chain reaction–Restriction fragment length polymorphism (PCR-RFLP) was performed for genotyping Xmn1 γGglobin polymorphism.ResultsA total of 30 (61.22%) patients were found to be responders, whereas the remaining 19 (38.78%) were non-responders. We found 33 patients with heterozygous (C/T) and three with homozygous mutant (T/T) genotype status. We obtained a statistically significant correlation (p < 0.001) between Xmn1 polymorphism and transfusion-free interval. Patients with Xmn1 polymorphism were found to be good responders for HU therapy and showed increased hemoglobin levels.ConclusionsOur findings indicate that HU is a potential drug candidate for thalassemia management, particularly HbE/β-thalassemia. The results hold implications in repurposing HU as an effective and efficient therapy for HbE/β-thalassemia.

scholarly journals Exploring the Drug Repurposing Versatility of Valproic Acid as a Multifunctional Regulator of Innate and Adaptive Immune Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-24 ◽  
Author(s):  
Rodolfo Soria-Castro ◽  
Alejandro Schcolnik-Cabrera ◽  
Gloria Rodríguez-López ◽  
Marcia Campillo-Navarro ◽  
Nahum Puebla-Osorio ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Valproic Acid ◽  
Immune Cells ◽  
Histone Deacetylases ◽  
Drug Repurposing ◽  
Promising Alternative ◽  
Expression Of Genes ◽  
Adaptive Immune Cells ◽  
Activation Of Transcription ◽  
Activation Mechanisms

Valproic acid (VPA) is widely recognized for its use in the control of epilepsy and other neurological disorders in the past 50 years. Recent evidence has shown the potential of VPA in the control of certain cancers, owed in part to its role in modulating epigenetic changes through the inhibition of histone deacetylases, affecting the expression of genes involved in the cell cycle, differentiation, and apoptosis. The direct impact of VPA in cells of the immune system has only been explored recently. In this review, we discuss the effects of VPA in the suppression of some activation mechanisms in several immune cells that lead to an anti-inflammatory response. As expected, immune cells are not exempt from the effect of VPA, as it also affects the expression of genes of the cell cycle and apoptosis through epigenetic modifications. In addition to inhibiting histone deacetylases, VPA promotes RNA interference, activates histone methyltransferases, or represses the activation of transcription factors. However, during the infectious process, the effectiveness of VPA is subject to the biological nature of the pathogen and the associated immune response; this is because VPA can promote the control or the progression of the infection. Due to its various effects, VPA is a promising alternative for the control of autoimmune diseases and hypersensitivity and needs to be further explored.

scholarly journals Molecular dynamics simulation and docking studies reveal NF-κB as a promising therapeutic drug target for COVID-19

2021 ◽  
Author(s):  
Shaban Ahmad ◽  
Piyush Bhanu ◽  
Jitendra Kumar ◽  
Ravi Kant Pathak ◽  
Dharmendra Mallick ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Protein Structures ◽  
Drug Repurposing ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Drug Candidate ◽  
Therapeutic Drug ◽  
Ligand Complex

Abstract Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rampant worldwide and is a deadly disease for humans. Our current work emphasizes on molecular dynamics simulation (MDS) targeting nuclear factor-kappa B (NF-κB), the well-known human transcription factor controlling innate and adaptive immunity, to understand its mechanism of action during COVID-19 in humans. NF-κB was interacted with the SARS-CoV-2 spike protein in an in silico MDS experiment, revealing the NF-κB site at which the SARS-CoV-2 spike protein interacts. We screened some known drugs via docking studies on NF-κB used as a receptor. The MDS software Schrodinger generated more than 2000 complexes from these compounds and using the SMILES format of these complexes, 243 structures were extracted and 411 conformers were generated. The drug used as a ligand that docked with NF-κB with the best docking score and binding affinity was Sulindac sodium as its trade name. Furthermore, RMSF data of sulindac sodium and NF-κB displayed minimal fluctuations in the protein structures, and the protein-ligand complex had reduced flexibility. Sulindac sodium is hence suggested as a suitable drug candidate for repurposing in clinical trials for SARS-CoV-2 infections. This drug potently blocked the spike protein’s interaction with NF-κB by inducing a conformational change in the latter. Arguably, NF-κB inaction is desired to have normal immunity and can possibly be retained using proposed drug. This work provides a significant lead for drug repurposing to combat SARS-CoV-2 and its various mutant forms and reveals new approach for controlling SARS-CoV-2-induced disease.

scholarly journals Modeling of SARS-CoV-2 treatment effects for informed drug repurposing

2021 ◽  
Author(s):  
Charlotte Kern ◽  
Verena Schöning ◽  
Carlos Chaccour ◽  
Felix Hammann
Keyword(s):  
Drug Repurposing ◽  
Antiviral Effect ◽  
Drug Candidate ◽  
Appreciable Effect ◽  
Viral Kinetics ◽  
Future Drug ◽  
Dosing Regimens ◽  
Clinical Trial Results

Abstract Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide.We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3-0.6 log units and exposure by 8.8-22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

Sign in / Sign up

Export Citation Format

Share Document