The role of interleukin-6 and janus kinases in the pathogenesis, and treatment of SARS-CoV-2 DOI Open Access
Nightingale Syabbalo

Journal of Lung Pulmonary & Respiratory Research, Journal Year: 2022, Volume and Issue: 9(1), P. 17 - 32

Published: Jan. 1, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a deadly pneumonia caused by an enveloped, single-stranded RNA betacoronavirus belonging to the coronaviridae family. Pathophysiologically, SARS-CoV-2 due severe hyperinflammatory host response coronavirus, resulting in overproduction of cytokines, chemokines, and growth factors macrophages, such as interleukin-1β (IL-1β), IL-2, IL-6, IL-8, IL-10, tumour necrosis factor-α. characterized diffuse alveolar damage direct infection type II pneumocytes, pulmonary edema, vascular occlusion, interstitial infiltrates, ventilation/perfusion mismatch, which rapidly progress hypoxemia, distress syndrome, multi-organ failure, death. The standard care Covid-19, includes high-flow nasal oxygen (HFNO), dexamethasone, remdesivir, mechanical ventilation or extracorporeal membrane oxygenation very cases. However, mortality exceptionally high even with these therapies. Covid-19 dysregulation, over-production including IL-1β, TNF-α. IL-6 plays key role orchestrating hyperinflammation cytokine storm, leads lung injury, failure. Interleukin-6 signaling via transmembrane receptor-α (mIL-6Rα), soluble IL-6Rα. Tocilizumab, sarilumab are IL-6Rα antagonists, have been issued emergency use authorization (EUA) FDA. Both biologics safe, effective treatment particularly patients requiring HFNO, support. Another therapeutic approach treat target downstream JAK/STAT pathway critical inciting immunopathological effects. Baricitimab tofacitinib granted EUA A systemic review has shown that JAK-inhibitors significantly decrease odd (P ˂ 0.0005), ICU admission 0.0005). Additionally JAKinibs increase odds for patient discharge within weeks P 0.00001). Tofacitinib reported lead lower risk failure death through day 28 than placebo hospitalized Covid-19. Barictinib addition care, dexamethasone was associated reduced adults Selective JAK inhibitors usual

Language: Английский

COVID-19 and the potential of Janus family kinase (JAK) pathway inhibition: A novel treatment strategy DOI Creative Commons
Mansoor Khaledi, Fatemeh Sameni,

Sheida Yahyazade

et al.

Frontiers in Medicine, Journal Year: 2022, Volume and Issue: 9

Published: Aug. 30, 2022

Recent evidence proposed that the severity of coronavirus disease 2019 (COVID-19) in patients is a consequence cytokine storm, characterized by increased IL-1β, IL-6, IL-18, TNF-α, and IFN-γ. Hence, managing storm drugs has been suggested for treatment with severe COVID-19. Several proinflammatory cytokines involved pathogenesis COVID-19 infection recruit distinct intracellular signaling pathway mediated JAKs. Consequently, JAK inhibitors, including baricitinib, pacritinib, ruxolitinib, tofacitinib, may represent an effective therapeutic strategy controlling to treat This study indicates mechanism JAK/STAT as well medications used inhibitors.

Language: Английский

Citations

14
Current Insights and Molecular Docking Studies of the Drugs under Clinical Trial as RdRp Inhibitors in COVID-19 Treatment DOI
Amita Verma, Pradeep Kumar,

Irine Pauly

et al.

Current Pharmaceutical Design, Journal Year: 2022, Volume and Issue: 28(46), P. 3677 - 3705

Published: Nov. 8, 2022

Study Background & Objective: After the influenza pandemic (1918), COVID-19 was declared a Vth by WHO in 2020. SARS-CoV-2 is an RNA-enveloped single-stranded virus. Based on structure and life cycle, Protease (3CLpro), RdRp, ACE2, IL-6, TMPRSS2 are major targets for drug development against COVID-19. Pre-existing several drugs (FDA-approved) used to inhibit above different diseases. In coronavirus treatment, these also clinical trial stages. Remdesivir (RdRp inhibitor) only FDA-approved medicine treatment. present study, using repurposing strategy, 70 preexisting or under molecules were scrutiny RdRp inhibitor potent treatment being surveyed via docking studies. Molecular simulation studies further confirmed binding mechanism stability of most compounds.Docking performed Maestro 12.9 module Schrodinger software over with as target remdesivir standard studies.The showed that many HIV protease inhibitors demonstrated remarkable interactions RdRp. such lopinavir ritonavir effective. Along these, AT-527, ledipasvir, bicalutamide, cobicistat improved scores. RMSD RMSF analyzed ledipasvir identified potential candidates corona disease.The approach provides new avenue

Language: Английский

Citations

10
A Clinical Update on SARS-CoV-2: Pathology and Development of Potential Inhibitors DOI Creative Commons
Desh Deepak Singh, Ihn Han, Eun Ha Choi

et al.

Current Issues in Molecular Biology, Journal Year: 2023, Volume and Issue: 45(1), P. 400 - 433

Published: Jan. 4, 2023

SARS-CoV-2 (severe acute respiratory syndrome) is highly infectious and causes severe distress syndrome (SARD), immune suppression, multi-organ failure. For SARS-CoV-2, only supportive treatment options are available, such as oxygen therapy, ventilator support, antibiotics for secondary infections, mineral fluid treatment, a significant subset of repurposed effective drugs. Viral targeted inhibitors the most suitable molecules, ACE2 (angiotensin-converting enzyme-2) RBD (receptor-binding domain) protein-based inhibitors, host proteases, viral proteases 3CLpro (3C-like proteinase) PLpro (papain-like protease), replicative enzymes, attachment to receptor TMPRSS2 (transmembrane serine proteinase 2), HR1 (Heptad Repeat 1)–HR2 2) interaction at S2 protein coronavirus, etc. Targeting cathepsin L proteinase, peptide analogues, monoclonal antibodies, chimaeras interferes with spike protein’s ability fuse membrane. Even tremendous progress made, creating drugs remains difficult. To develop COVID-19 alternatives, clinical studies examining variety therapy categories, including antivirals, cell-based diagnostic medicines, more. In this article, we discuss recent updates on infection, characteristics, diagnosis, immunopathology, new emergence variant, various approaches drug development options. The therapies has been complicated by global occurrence many mutations. Discussion manuscript will provide insight into pathophysiology development.

Language: Английский

Citations

6
Forced degradation study of baricitinib and structural characterization of its degradation impurities by high‐resolution mass spectrometry and nuclear magnetic resonance spectroscopy DOI

Sowmya Chaganti,

Vivek Dhiman,

Vijaya Madhyanapu Golla

et al.

Rapid Communications in Mass Spectrometry, Journal Year: 2023, Volume and Issue: 37(18)

Published: Aug. 7, 2023

Baricitinib (BARI), an inhibitor of Janus kinases 1 and 2 (JAK 1/2), is used for the treatment rheumatoid arthritis COVID-19. The present study focuses on establishing forced degradation behavior BARI under different conditions (hydrolysis, oxidation, photolysis) following International Council Harmonization (ICH) guidelines Q1A (R2)-Stability testing new drug substances products Q1B-Photostability products. This helps in monitoring quality safety its product development.Prior to conducting study, silico profile was predicted by Zeneth. Reversed-phase high-performance liquid chromatography employing a gradient program identification separation impurities with InertSustain C8 column (4.6 × 250 mm, 5 μm). mobile phases were 10 mM ammonium formate (pH 2.89) acetonitrile. High-resolution mass spectrometry (HRMS) structural elucidation impurities.BARI labile hydrolytic (acidic, basic, neutral) photolytic which yielded it stable oxidative (H2 O2 ) conditions. separated characterized HRMS respective pathways proposed. generated information helped propose mechanism formation impurities. Additionally, one-dimensional two-dimensional nuclear magnetic resonance spectroscopy characterization two major impurities.The carried out accordance ICH Q1B guidelines, resulted In our analysis, three matching Zeneth predictions. tools, DEREK Nexus® SARAH Nexus®, predicting toxicity mutagenicity Overall, this sheds light BARI's storage circumstances.

Language: Английский

Citations

4
JAK-STAT signaling as an ARDS therapeutic target: Status and future trends DOI

Yuanteng Zhang,

Zizheng Gao,

Feng Jiang

et al.

Biochemical Pharmacology, Journal Year: 2022, Volume and Issue: 208, P. 115382 - 115382

Published: Dec. 14, 2022

Language: Английский

Citations

6
Baricitinib and tofacitinib off-target profile, with a focus on Alzheimer’s disease DOI Creative Commons
Maria Luisa Faquetti, Laura Slappendel, Hélène Bigonne

et al.

Published: Aug. 3, 2023

Introduction: Janus Kinase (JAK) inhibitors were recently identified as promising drug candidates for repurposing in Alzheimer’s disease (AD) due to their capacity suppress inflammation via modulation of JAK/STAT signalling pathways. Besides interaction with primary therapeutic targets, JAK inhibitor drugs frequently interact unintended, often unknown, biological off-targets, leading associated effects. Nevertheless, the relevance off-target interactions context AD remains unclear. Methods: Putative off-targets baricitinib and tofacitinib predicted using a machine learning (ML) approach. After screening scientific literature, filtered based on AD. Targets that had not been previously or subsequently tested biochemical cell-based assays. From those, active concentrations compared bioavailable brain by physiologically pharmacokinetic (PBPK) modelling. Results: With aid ML vitro activity assays, we two enzymes unknown be inhibited baricitinib, namely casein kinase 2 subunit alpha (CK2-alpha-2) dual leucine zipper (MAP3K12), both Kd values 5.8 uM. Predicted maximum tissue PBPK modelling range from 1.3 23 nM, which is three orders magnitude below corresponding binding constant. Conclusion: In this study, extended list are potentially relevant progression distribution brain. The results suggest low likelihood successful permeability, even at recommended daily dose. While additional research needed evaluate potential impact AD, combined approach target prediction, confirmation, may help prioritise high being effectively repurposed

Language: Английский

Citations

2
Computational insight of repurpose drug for treatment of COVID-19: a CDFT approach DOI
Prabhat Ranjan, Tanmoy Chakraborty

Theoretical Chemistry Accounts, Journal Year: 2023, Volume and Issue: 143(1)

Published: Dec. 27, 2023

Language: Английский

Citations

2
Molecular Evolution of Severe Acute Respiratory Syndrome Coronavirus 2: Hazardous and More Hazardous Strains Behind the Coronavirus Disease 2019 Pandemic and Their Targeting by Drugs and Vaccines DOI Creative Commons
Hardeep Singh Tuli, Katrin Sak, Poonam Aggarwal

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2021, Volume and Issue: 11

Published: Dec. 14, 2021

Within almost the last 2 years, world has been shaken by coronavirus disease 2019 (COVID-19) pandemic, which affected lives of all people. With nearly 4.92 million deaths October 19, 2021, and serious health damages in millions people, COVID-19 most global challenge after Second World War. Besides lost long-term problems, devastating impact on economics, education, culture will probably leave a lasting impression future. Therefore, actual extent losses become obvious only years. Moreover, despite availability different vaccines vaccination programs, it is still impossible to forecast what next steps virus are or how near we end pandemic. In this article, route molecular evolution severe acute respiratory syndrome (SARS-CoV-2) thoroughly compiled, highlighting changes that undergone during years discussing approaches medical community undertaken fight against virus-induced damages.

Language: Английский

Citations

4
Current Treatments for COVID-19: Application of Supercritical Fluids in the Manufacturing of Oral and Pulmonary Formulations DOI Creative Commons
Helga K. Ruiz, Dolores R. Serrano, Lourdes Calvo

et al.

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(11), P. 2380 - 2380

Published: Nov. 4, 2022

Even though more than two years have passed since the emergence of COVID-19, research for novel or repositioned medicines from a natural source chemically synthesized is still an unmet clinical need. In this review, application supercritical fluids to development repurposed COVID-19 and their secondary bacterial complications will be discussed. We envision three main applications in field: (i) drug micronization, (ii) fluid extraction bioactives (iii) sterilization. The micronization techniques can help improve aqueous solubility oral bioavailability drugs, consequently, need lower doses elicit same pharmacological effects result reduction dose administered adverse effects. addition, between 1 5 µm aid manufacturing pulmonary formulations target directly lung. Supercritical also enormous potential bioactive compounds, which shown remarkable efficacy against COVID-19. Finally, successful inactivation viruses opens up opportunity sterilization healthcare field.

Language: Английский

Citations

3
Drug Repurposing in Inflammatory Disorders DOI

Keshari Kumar Sriwastawa,

Vaishnavi Sawkare,

Ayaan Ansari

et al.

Drug repurposing, Journal Year: 2024, Volume and Issue: unknown, P. 93 - 107

Published: Jan. 1, 2024

Language: Английский

Citations

0