Small molecules in the treatment of COVID-19

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Language: Английский

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Sensitivity to Vaccines, Therapeutic Antibodies, and Viral Entry Inhibitors and Advances To Counter the SARS-CoV-2 Omicron Variant

Clinical Microbiology Reviews, Journal Year: 2022, Volume and Issue: 35(3)

Published: June 6, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps evolving and mutating into newer variants over time, which gain higher transmissibility, disease severity, spread in communities at a faster rate, resulting multiple waves of surge Coronavirus Disease 2019 (COVID-19) cases. A highly mutated transmissible SARS-CoV-2 Omicron variant has recently emerged, driving the extremely high peak infections almost all continents an unprecedented speed scale. The evades protection rendered by vaccine-induced antibodies natural infection, as well overpowers antibody-based immunotherapies, raising concerns current effectiveness available vaccines monoclonal therapies. This review outlines most recent advancements studying virology biology variant, highlighting its increased resistance to therapeutics immune escape against vaccines. However, is sensitive viral fusion inhibitors targeting HR1 motif spike protein, enzyme inhibitors, involving endosomal pathway, ACE2-based entry inhibitors. variant-associated infectivity mechanisms are essentially distinct from previous characterized variants. Innate sensing evasion T cell immunity virus provide new perspectives vaccine drug development. These findings important for understanding advances developing vaccines, therapies, more effective strategies mitigate transmission or next concern.

Language: Английский

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Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions

MedComm, Journal Year: 2022, Volume and Issue: 3(3)

Published: Aug. 1, 2022

The 2019 coronavirus disease (COVID-19) pandemic has become a global crisis. In the immunopathogenesis of COVID-19, SARS-CoV-2 infection induces an excessive inflammatory response in patients, causing cytokine storm severe cases. Cytokine leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is important cause COVID-19 progression even death. Among them, activation pathways major factor generating storms dysregulated immune responses, closely related severity viral infection. Therefore, elucidation signaling pathway providing otential therapeutic targets treatment strategies against COVID-19. Here, we discuss pathogenesis including induction, function, downstream signaling, as well existing potential interventions targeting these cytokines or pathways. We believe that comprehensive understanding regulatory dysregulation inflammation will help develop better clinical therapy effectively control diseases, such

Language: Английский

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Human lungs show limited permissiveness for SARS-CoV-2 due to scarce ACE2 levels but virus-induced expansion of inflammatory macrophages

European Respiratory Journal, Journal Year: 2022, Volume and Issue: 60(6), P. 2102725 - 2102725

Published: June 21, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis still elusive.Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied infected human lung explants adult stem cell derived organoids correlate related host factors with tropism, propagation, virulence compared SARS-CoV, influenza Middle East (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used validate ex vivo results.We provide evidence that expression must be considered scarce, thereby limiting propagation alveolus. Instead, lungs COVID-19 samples showed macrophages frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake a inflammatory anti-viral activation, especially "inflammatory macrophages", comparable those induced by SARS-CoV MERS-CoV, but different from NL63 infection.Collectively, our findings indicate severe injury probably results macrophage-triggered rather than viral of compartment.

Language: Английский

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Nanoparticle Delivery Platforms for RNAi Therapeutics Targeting COVID-19 Disease in the Respiratory Tract

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(5), P. 2408 - 2408

Published: Feb. 22, 2022

Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across globe. At present, Food and Drug Administration (FDA) issued emergency approval for use some antiviral drugs. However, these drugs still have limitations in specific treatment COVID-19, as such, new strategies urgently need to be developed. RNA-interference-based gene therapy provides tractable target treatment. Ensuring cell-specific targeted delivery is important success therapy. The nanoparticles (NPs) carriers small interfering RNA (siRNAs) tissues or organs human body could play crucial role infections, such COVID-19. In this review, we describe variety novel nanocarriers, lipid NPs, star polymer glycogen summarize pre-clinical/clinical progress nanoparticle platforms siRNA delivery. We also discuss application various NP-capsulated therapeutics SARS-CoV-2 infection, challenges with targeting local lung, inhalation devices used therapeutic administration. currently available animal models that are preclinical assessment Advances field potential treatments disease adapted treat range diseases.

Language: Английский

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Cytokines and microRNAs in SARS-CoV-2: What do we know?

Molecular Therapy — Nucleic Acids, Journal Year: 2022, Volume and Issue: 29, P. 219 - 242

Published: June 25, 2022

Language: Английский

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Treatment with quercetin inhibits SARS-CoV-2 N protein-induced acute kidney injury by blocking Smad3-dependent G1 cell-cycle arrest

Molecular Therapy, Journal Year: 2022, Volume and Issue: 31(2), P. 344 - 361

Published: Dec. 12, 2022

Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which induces AKI are largely unknown, treatment remains ineffective. Here, we report kidney-specific overexpressing N gene AKI, including tubular necrosis elevated levels of serum creatinine BUN 8-week-old diabetic db/db mice, become worse those with older age (16 weeks) underlying disease (DKD). Treatment quercetin, a purified product from traditional Chinese medicine (TCM) effective patients, significantly inhibit protein-induced mice or without DKD. Mechanistically, quercetin block the binding protein to Smad3, thereby inhibiting Smad3 signaling Smad3-mediated cell death via p16-dependent G1 cell-cycle arrest mechanism vivo vitro. In conclusion, is pathogenic severe particularly pre-existing DKD, Smad3-dependent mechanism. Importantly, identify may be an TCM compound capable by blocking N-Smad3-mediated pathway.

Language: Английский

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Galectin 3‐binding protein (LGALS3BP) depletion attenuates hepatic fibrosis by reducing transforming growth factor‐β1 (TGF‐β1) availability and inhibits hepatocarcinogenesis

Cancer Communications, Journal Year: 2024, Volume and Issue: 44(10), P. 1106 - 1129

Published: July 28, 2024

Abstract Background Increased Galectin 3‐binding protein (LGALS3BP) serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma (HCC). Considering crucial role transforming growth factor‐β1 (TGF‐β1) in emergence these diseases, present study tested hypothesis that LGALS3BP regulates TGF‐β1 signaling pathway. Methods The expression TGFB1 were analyzed patients with metabolic dysfunction‐associated steatohepatitis (MASH) HCC. Multiple omics techniques, such as RNA‐sequencing, transposase‐accessible chromatin‐sequencing assay, liquid chromatography‐tandem mass spectrometry proteomics, identify regulatory mechanisms for LGALS3BP‐TGF‐β1 axis. effects altered by investigated conditional ‐knockin ‐knockout mice. Results In MASH HCC, exhibited positive correlations. Stimulation inflammatory cytokine interferon α HCC cells or ectopic overexpression hepatocytes promoted TGFB1. Aggravated was observed livers hepatocyte‐specific mice, increased levels. directly bound assembled integrin αV, an integral mediator required releasing active from extracellular latent complex rearranged F‐actin cytoskeleton. released activated JunB transcription factor, which turn feedback loop. deletion downregulated CCl 4 induced fibrosis. Moreover, depletion hindered hepatocarcinogenesis limiting availability fibrogenic TGF‐β1. Conclusion plays a carcinogenesis controlling pathway, making it promising therapeutic target TGF‐β1‐related diseases.

Language: Английский

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Repurposing Anticancer Drugs Targeting the MAPK/ERK Signaling Pathway for the Treatment of Respiratory Virus Infections

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 6946 - 6946

Published: June 25, 2024

Respiratory virus infections remain a significant challenge to human health and the social economy. The symptoms range from mild rhinitis nasal congestion severe lower respiratory tract dysfunction even mortality. efficacy of therapeutic drugs targeting viruses varies, depending upon infection time drug resistance engendered by high frequency viral genome mutations, necessitating development new strategies. MAPK/ERK pathway that was well delineated in 1980s represents classical signaling cascade, essential for cell proliferation, survival, differentiation. Since this is constitutively activated many cancers oncogenes, several inhibiting Raf/MEK/ERK have been developed currently used anticancer treatment. Two decades ago, it reported such as HIV influenza could exploit host cellular their replication. Thus, would be feasible repurpose category inhibitors treatment infections. advantage genes are not easy mutate rarely occurs during short-period viruses. Therefore, review we will summarize research progress on role amplification discuss potential (MEK inhibitors)

Language: Английский

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Novel quinazoline sulfonamide-based scaffolds modulate methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in immunodeficient irradiated model: Regulatory role of TGF-β

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 150, P. 107559 - 107559

Published: June 12, 2024

Language: Английский

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