Current Trends and Future Approaches in Small-Molecule Therapeutics for COVID-19.
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ABSTRACT:
SUBMITTER: Laws M
PROVIDER: S-EPMC7611096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia ("cytokine storm"). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19's immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.
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Project description:The on-going pandemic of COVID-19 wreaked by a viral infection of SARS-CoV-2, has generated a catastrophic plight across the globe. Interestingly, one of the hallmarks of COVID-19 is the so-called 'cytokine storm' due to attack of SARS-Cov-2 in the lungs. Considering, mesenchymal stem cells (MSCs) therapy could contribute against SARS-CoV-2 viruses attack because of their immune modulatory and anti-inflammatory ability linked to their stemness, to the arsenal of treatments for COVID-19. Another novel therapeutic strategies include the blockade of rampant generation of pro-inflammatory mediators like acute respiratory distress syndrome (ARDS), degradation of viral protein capsids by PROTACs, composed of Ubiquitin-proteasome framework, and ubiquitination-independent pathway directing the SARS-CoV-2 nucleocapsid protein (nCoV N) and proteasome activator (PA28γ), etc. This review is consequently an endeavour to highlight the several aspects of COVID-19 with incorporation of important treatment strategies discovered to date and putting the real effort on the future directions to put them into the perspective.
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Project description:Low back pain (LBP) is a major reason for disability, and symptomatic intervertebral disc (IVD) degeneration (IDD) contributes to roughly 40% of all LBP cases. Current treatment modalities for IDD include conservative and surgical strategies. Unfortunately, there is a significant number of patients in which conventional therapies fail with the result that these patients remain suffering from chronic pain and disability. Furthermore, none of the current therapies successfully address the underlying biological problem - the symptomatic degenerated disc. Both spinal fusion as well as total disc replacement devices reduce spinal motion and are associated with adjacent segment disease. Thus, there is an unmet need for novel and stage-adjusted therapies to combat IDD. Several new treatment options aiming to regenerate the IVD are currently under investigation. The most common approaches include tissue engineering, growth factor therapy, gene therapy, and cell-based treatments according to the stage of degeneration. Recently, the regenerative activity of small molecules (low molecular weight organic compounds with less than 900 daltons) on IDD was demonstrated. However, small molecule-based therapy in IDD is still in its infancy due to limited knowledge about the mechanisms that control different cell signaling pathways of IVD homeostasis. Small molecules can act as anti-inflammatory, anti-apoptotic, anti-oxidative, and anabolic agents, which can prevent further degeneration of disc cells and enhance their regeneration. This review pursues to give a comprehensive overview of small molecules, focusing on low molecular weight organic compounds, and their potential utilization in patients with IDD based on recent in vitro, in vivo, and pre-clinical studies.
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Project description:Coronavirus disease 2019 (COVID-19) has made a global impact on the daily lives of humanity, devastating health systems, and cataclysmically affecting the world's economy. Currently, the Standard Public Health Protective practices consist of but are not limited to wearing masks, social distancing, isolating sick and exposed people, and contact tracing. Scientists around the globe undertook swift scientific efforts to develop safe and effective therapeutics and vaccines to combat COVID-19. Presently, as of mid-March 2022, 57.05% of the world population have been fully vaccinated, and 65.3% of the United States of America's (USA) total population have been fully vaccinated while 76.7% have received at least one dose of the vaccine. This article explores the various vaccines created through modern science and technology, including their safety, efficacy, and mechanism of action. Although the vaccines produced are up to 95.0% efficacious, their efficacy wanes over time, underscoring the need for booster doses. Also, vaccination has not been able to prevent "breakthrough" infections. The limitations of the SARS-CoV-2 vaccines indicate that further measures are required to ensure a firm control of the COVID-19 pandemic. Therefore, the Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the use of certain therapeutic agents because they have shown remarkable clinical outcomes. Several therapeutic agents for the treatment of mild-to-moderate COVID-19 include Gilead's remdesivir, Regeneron's casirivimab and imdevimab combination, Eli Lilly's baricitinib and remdesivir combination, Pfizer's co-packaged nirmatrelvir tablets and ritonavir tablets, and Merck's molnupiravir capsules. Hence concerted efforts in early and accurate diagnosis, education on the COVID-19 virulence, transmission and preventive measures, global vaccination, and therapeutic agents could bring this COVID-19 pandemic under control across the globe.
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