Repurposing Interleukin-6 Inhibitors to Combat COVID-19.
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ABSTRACT:
SUBMITTER: Kato S
PROVIDER: S-EPMC8221576 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsA newly emerged Human Coronavirus (HCoV) is reported two months ago in Wuhan, China (COVID-19). Until today >2700 deaths from the 80,000 confirmed cases reported mainly in China and 40 other countries. Human to human transmission is confirmed for COVID-19 by China a month ago. Based on the World Health Organization (WHO) reports, SARS HCoV is responsible for >8000 cases with confirmed 774 deaths. Additionally, MERS HCoV is responsible for 858 deaths out of about 2500 reported cases. The current study aims to test anti-HCV drugs against COVID-19 RNA dependent RNA polymerase (RdRp).Materials and methodsIn this study, sequence analysis, modeling, and docking are used to build a model for Wuhan COVID-19 RdRp. Additionally, the newly emerged Wuhan HCoV RdRp model is targeted by anti-polymerase drugs, including the approved drugs Sofosbuvir and Ribavirin.Key findingsThe results suggest the effectiveness of Sofosbuvir, IDX-184, Ribavirin, and Remidisvir as potent drugs against the newly emerged HCoV disease.SignificanceThe present study presents a perfect model for COVID-19 RdRp enabling its testing in silico against anti-polymerase drugs. Besides, the study presents some drugs that previously proved its efficiency against the newly emerged viral infection.
| S-EPMC7089605 | biostudies-literature
Project description:The outbreak of COVID-19, the pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an intense search for treatments by the scientific community. In the absence of a vaccine, the goal is to target the viral life cycle and alleviate the lung-damaging symptoms of infection, which can be life-threatening. There are numerous protein kinases associated with these processes that can be inhibited by FDA-approved drugs, the repurposing of which presents an alluring option as they have been thoroughly vetted for safety and are more readily available for treatment of patients and testing in clinical trials. Here, we characterize more than 30 approved kinase inhibitors in terms of their antiviral potential, due to their measured potency against key kinases required for viral entry, metabolism, or reproduction. We also highlight inhibitors with potential to reverse pulmonary insufficiency because of their anti-inflammatory activity, cytokine suppression, or antifibrotic activity. Certain agents are projected to be dual-purpose drugs in terms of antiviral activity and alleviation of disease symptoms, however drug combination is also an option for inhibitors with optimal pharmacokinetic properties that allow safe and efficacious co-administration with other drugs, such as antiviral agents, IL-6 blocking agents, or other kinase inhibitors.
| S-EPMC7417114 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus 2, famous as COVID-19, has recently emerged as a novel virus and imposed an unrecoverable loss to global health and the economy. At present, no effective drug against COVID-19 is available and currently available viral drugs targeting the viral key proteins of related RNA viruses have been found ineffective against COVID-19. This study evaluated the inhibitors of the viral proteases and other structural proteins, including Mpro (Main protease), RdRp (RNA-dependent RNA polymerase), and spike glycoprotein from synthetic and herbal sources. The molecular docking-based approach was used to identify and evaluate the putative inhibitors of key proteins involved in viral replication and survival. Furthermore, the pharmaceutical properties of these inhibitors were explored to predict the drug suitability as a therapeutic agent against COVID-19 by considering adsorption, distribution, metabolism, and excretion (ADME) using Lipinski's rule or SwissADME. Trandolapril, Benazepril, and Moexipril were evaluated as the best non-carcinogenic and non-toxic potential inhibitors of spike glycoprotein, Mpro, and RdRp, respectively. The drugs showed significant binding affinities against the active sites of respective SARS_CoV-2 target proteins; hence, they can be used as potential therapeutic agents for the treatment of COVID-19.
| S-EPMC8367655 | biostudies-literature
Project description:The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that originated in Chinese city of Wuhan has caused around 906,092 deaths and 28,040,853 confirmed cases worldwide (https://covid19.who.int/, 11 September 2020). In a life-threatening situation, where there is no specific and licensed anti-COVID-19 vaccine or medicine available; the repurposed drug might act as a silver bullet. Currently, more than 211 vaccines, 80 antibodies, 31 antiviral drugs, 35 cell-based, 6 RNA-based and 131 other drugs are in clinical trials. It is therefore utter need of the hour to develop an effective drug that can be used for the treatment of COVID-19 before a vaccine can be developed. One of the best-characterized and attractive drug targets among coronaviruses is the main protease (3CLpro). Therefore, the current study focuses on the molecular docking analysis of TAT-peptide47-57 (GRKKRRQRRRP)-conjugated repurposed drugs (i.e., lopinavir, ritonavir, favipiravir, and hydroxychloroquine) with SARS-CoV-2 main protease (3CLpro) to discover potential efficacy of TAT-peptide (TP) - conjugated repurposing drugs against SARS-CoV-2. The molecular docking results validated that TP-conjugated ritonavir, lopinavir, favipiravir, and hydroxychloroquine have superior and significantly enhanced interactions with the target SARS-CoV-2 main protease. In-silico approach employed in this study suggests that the combination of the drug with TP is an excelling alternative to develop a novel drug for the treatment of SARS-CoV-2 infected patients. The development of TP based delivery of repurposing drugs might be an excellent approach to enhance the efficacy of the existing drugs for the treatment of COVID-19. The predictions from the results obtained provide invaluable information that can be utilized for the choice of candidate drugs for in vitro, in vivo and clinical trials. The outcome from this work prove crucial for exploring and developing novel cost-effective and biocompatible TP conjugated anti-SARS-CoV-2 therapeutic agents in immediate future.
| S-EPMC7527303 | biostudies-literature
Project description:The emergence and rapid spreading of novel SARS-CoV-2 across the globe represent an imminent threat to public health. Novel antiviral therapies are urgently needed to overcome this pandemic. Given the significant role of the main protease of Covid-19 for virus replication, we performed a drug-repurposing study using the recently deposited main protease structure, 6LU7. For instance, pharmacophore- and e-pharmacophore-based hypotheses such as AARRH and AARR, respectively, were developed using available small molecule inhibitors and utilized in the screening of the DrugBank repository. Further, a hierarchical docking protocol was implemented with the support of the Glide algorithm. The resultant compounds were then examined for their binding free energy against the main protease of Covid-19 by means of the Prime-MM/GBSA algorithm. Most importantly, the machine learning-based AutoQSAR algorithm was used to predict the antiviral activities of resultant compounds. The hit molecules were also examined for their drug-likeness and toxicity parameters through the QikProp algorithm. Finally, the hit compounds activity against the main protease was validated using molecular dynamics simulation studies. Overall, the present analysis yielded two potential inhibitors (DB02986 and DB08573) that are predicted to bind with the main protease of Covid-19 better than currently used drug molecules such as N3 (cocrystallized native ligand), lopinavir, and ritonavir.
| S-EPMC8250478 | biostudies-literature
Project description:AimToday, humanity is living through the third serious coronavirus outbreak in less than 20 years, following SARS in 2002-2003 and MERS in 2012. While the final cost on human lives and world economy remains unpredictable, the timely identification of a suitable treatment and the development of an effective vaccine remain a significant challenge and will still require time. The aim of this study is to show that the global collective effort to control the coronavirus pandemic (Covid 19) should also consider alternative therapeutic methods, and national health systems should quickly endorse the validity of proven homeopathic treatments in this war against coronavirus disease.Subject and methodsWith the help of mathematics, we will show that the fundamental therapeutic law on which homeopathy is founded can be proved.ResultsThe mathematical proof of the law of similarity justifies perfectly the use of ultra - high diluted succussed solution products as major tools in the daily practices of homeopathy.ConclusionIt is now time to end prejudice and adopt in this fight against Covid-19 alternative therapeutic techniques and practices that historically have proven effective in corresponding situations.
| S-EPMC7272237 | biostudies-literature
Project description:COVID-19 has now been declared a pandemic and new treatments are urgently needed as we enter a phase beyond containment. Developing new drugs from scratch is a lengthy process, thus impractical to face the immediate global challenge. Drug repurposing is an emerging strategy where existing medicines, having already been tested safe in humans, are redeployed to combat difficult-to-treat diseases. While using such repurposed drugs individually may ultimately not yield a significant clinical benefit, carefully combined cocktails could be very effective, as was for HIV in the 1990s; the urgent question now being which combination.
| S-EPMC7117595 | biostudies-literature
Project description:Cytokine storm syndrome (CSS) is a severe complication of inflammatory immune diseases or treatment of malignancies; it may also appear during the progression of COVID-19. CSS is caused by dysregulation of the synthesis of cytokines, including pro-inflammatory, regulatory, and anti-inflammatory cytokines and chemokines, leading to pathologic activation of innate and adaptive (Th1 and Th17 mediated) immunity. Interleukin-6 (IL-6) plays an important role in the pathogenesis of CSS. The significant role of IL-6 in pathogenesis of COVID-19 was confirmed in a range of studies, which showed that the plasma concentration of IL-6 was increased in patients with severe COVID-19. Currently, IL-6 inhibitor therapeutics are not yet approved for the treatment of COVID-19; however, these medicines, including tocilizumab (TCZ) are used off-label for the treatment of patients with severe COVID-19, including life-threatening conditions. The role of IL-6 in the pathogenesis of CSS during COVID-19 is important however, a number of related issues are not yet clear. These issues include the indications for treatment with IL-6 inhibitors, as well as the estimation of risk associated with the disease, outcomes, treatment options, and adverse drug reactions. The development of personalized immunomodulatory therapy, with respect to the role of cytokines in pathogenesis, requires the studies that aimed to find other relevant therapeutic targets for the treatment of CSS in patients with COVID-19. These therapeutic targets include inhibition of IL-1, IL-6, TNF?, GM-CSF, IFN?, IL-17, IL-18, and also activation of the complement system. The challenge of CSS in patients with COVID-19 is identifying the correct scientific targets and developing clinical trials aimed to evaluate the pathogenesis and treat immune-mediated inflammatory diseases (IMIDs). Hopefully, the significant efforts of scientists and physicians across the globe will improve the prognosis in COVID-19 patients and provide useful information on IMIDs required to support the struggle for treating potential viral outbreaks, and treatment of well-known IMIDs.
| S-EPMC7455113 | biostudies-literature
Project description:Using the crystal structure of SARS-CoV-2 papain-like protease (PLpro) as a template, we developed a pharmacophore model of functional centers of the PLpro inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search identified 147 compounds that can be potential inhibitors of SARS-CoV-2 PLpro. The conformations of these compounds underwent 3D fingerprint similarity clusterization, followed by docking of possible conformers to the binding pocket of PLpro. Docking of random compounds to the binding pocket of protease was also done for comparison. Free energies of the docking interaction for the selected compounds were lower than for random compounds. The drug list obtained includes inhibitors of HIV, hepatitis C, and cytomegalovirus (CMV), as well as a set of drugs that have demonstrated some activity in MERS, SARS-CoV, and SARS-CoV-2 therapy. We recommend testing of the selected compounds for treatment of COVID-19.
| S-EPMC7505060 | biostudies-literature
Project description:Drug repurposing or repositioning is a technique whereby existing drugs are used to treat emerging and challenging diseases, including COVID-19. Drug repurposing has become a promising approach because of the opportunity for reduced development timelines and overall costs. In the big data era, artificial intelligence (AI) and network medicine offer cutting-edge application of information science to defining disease, medicine, therapeutics, and identifying targets with the least error. In this Review, we introduce guidelines on how to use AI for accelerating drug repurposing or repositioning, for which AI approaches are not just formidable but are also necessary. We discuss how to use AI models in precision medicine, and as an example, how AI models can accelerate COVID-19 drug repurposing. Rapidly developing, powerful, and innovative AI and network medicine technologies can expedite therapeutic development. This Review provides a strong rationale for using AI-based assistive tools for drug repurposing medications for human disease, including during the COVID-19 pandemic.
| S-EPMC7500917 | biostudies-literature