Review of COVID-19 Therapeutics by Mechanism: From Discovery to Approval

Journal of Korean Medical Science, Journal Year: 2024, Volume and Issue: 39(14)

Published: Jan. 1, 2024

The global research and pharmaceutical community rapidly mobilized to develop treatments for coronavirus disease 2019 (COVID-19). Existing have been repurposed new drugs emerged. Here we summarize mechanisms clinical trials of COVID-19 therapeutics approved or in development. Two reviewers, working independently, reviewed published data vaccines drugs, as well developmental pipelines, using databases from the following organizations: United States Food Drug Administration (US-FDA), European Medicines Agency (EMA), Japanese Pharmaceutical Medical Devices (PMDA), ClinicalTrials.gov. In all, 387 were found initial review. After removing unrelated 66 selected, including 17 49 under These classified into six categories: 1) targeting viral life cycle 2) Anti-severe acute respiratory syndrome 2 Monoclonal Antibodies, 3) immunomodulators, 4) anti-coagulants, 5) COVID-19-induced neuropathy 6) other therapeutics. Among development are following: 6 cycle, 12 immunosuppression immunostimulants, HIF-PHD 3 GM-CSF 5 others. This review provides insight action, properties, indications medications.

Language: Английский

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C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(12)

Published: April 27, 2023

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved pathophysiology. signaling increased locally lung, especially neutrophils of critically ill patients compared influenza infection, as well lung tissue K18-hACE2 Tg mice (Tg mice) infected SARS-CoV-2. Genetic pharmacological inhibition C5aR1 ameliorated immunopathology Tg-infected mice. Mechanistically, found drives neutrophil extracellular traps-dependent (NETs-dependent) immunopathology. These data confirm role indicate antagonists useful for treatment.

Language: Английский

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Discovery of PL^pro and M^pro Inhibitors for SARS-CoV-2

ACS Omega, Journal Year: 2023, Volume and Issue: 8(25), P. 22603 - 22612

Published: June 14, 2023

There are very few small-molecule antivirals for SARS-CoV-2 that either currently approved (or emergency authorized) in the US or globally, including remdesivir, molnupiravir, and paxlovid. The increasing number of variants have appeared since outbreak began over three years ago raises need continual development updated vaccines orally available order to fully protect treat population. viral main protease (Mpro) papain-like (PLpro) key replication; therefore, they represent valuable targets antiviral therapy. We herein describe an vitro screen performed using 2560 compounds from Microsource Spectrum library against Mpro PLpro attempt identify additional hits could be repurposed SARS-CoV-2. subsequently identified 2 8 PLpro. One these was quaternary ammonium compound cetylpyridinium chloride with dual activity (IC50 = 2.72 ± 0.09 μM IC50 7.25 0.15 Mpro). A second inhibitor selective estrogen receptor modulator raloxifene 3.28 0.29 42.8 6.7 additionally tested several kinase inhibitors olmutinib 0.54 0.04 μM), bosutinib 4.23 0.28 crizotinib 3.81 dacominitinib 3.33 0.06 μM) as first time. In some cases, molecules also been by others this virus, we used Calu-3 cells infected results suggest drugs can promising proteases, cases validated their activity. identification known targeting may provide new repurposing opportunities starting points chemical optimization.

Language: Английский

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High-Throughput Empirical and Virtual Screening To Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Therapy resistance in breast cancer is increasingly attributed to polyploid giant cells (PGCCs), which arise through whole genome doubling and exhibit heightened resilience standard treatments. Characterized by enlarged nuclei increased DNA content, these tend be dormant under therapeutic stress, driving disease relapse. Despite their critical role resistance, strategies effectively target PGCCs are limited, largely due the lack of high-throughput methods for assessing viability. Traditional assays sensitivity needed detect PGCC-specific elimination, prompting development novel approaches. To address this challenge, we developed a single-cell morphological analysis workflow designed differentiate compounds that selectively inhibit non-PGCCs, PGCCs, or both. Using method, screened library 2726 FDA Phase 1-approved drugs, identifying promising anti-PGCC candidates, including proteasome inhibitors, FOXM1, CHK, macrocyclic lactones. Notably, RNA-Seq treated with lactone Pyronaridine revealed AXL inhibition as potential strategy targeting PGCCs. Although our pipeline powerful, empirical testing all existing impractical inefficient. overcome limitation, trained machine learning model predict efficacy silico, integrating chemical fingerprints compound descriptions from prior publications databases. The demonstrated high correlation experimental outcomes predicted efficacious an expanded over 6,000 drugs. Among top-ranked predictions, experimentally validated five potent PGCC inhibitors using cell lines patient-derived models. These findings underscore synergistic screening learning-based virtual accelerate discovery therapies, particularly therapy-resistant cancer.

Language: Английский

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Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial

EBioMedicine, Journal Year: 2022, Volume and Issue: 86, P. 104322 - 104322

Published: Nov. 1, 2022

This exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19.This phase 2, single centre, randomised, open-label, clinical trial was conducted South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic aged 18-65 years, RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir nitazoxanide (FPV + NTZ), sofosbuvir-daclatasvir (SOF-DCV). The primary endpoint the incidence of viral clearance, i.e., proportion patients a negative on day 7, compared using log-binomial model modified intention-to-treat (mITT) population.The mITT population included 186 patients: mean age (SD) 34.9 (10.3) body weight 78.2 (17.1) kg. Day 7 clearance rates (n/N; risk ratio [95% CI]) were: 34.2% (13/38), ASAQ 38.5% (15/39; 0.80 [0.44, 1.47]), PA 30.3% (10/33; 0.69 [0.37, 1.29]), FPV NTZ 27.0% (10/37; 0.60 [0.31, 1.18]) SOF-DCV 23.5% (8/34; 0.47 [0.22, 1.00]). Three lower respiratory tract infections occurred (PA 6.1% [2/33]; 2.9% [1/34]); two required hospitalisation (PA, SOF-DCV). There no deaths. Adverse events 55.3% (105/190) patients, including one serious adverse event (pancytopenia; NTZ).There statistical difference for any regimen SOC. All treatments well tolerated.Medicines Malaria Venture, funding from UK Foreign, Commonwealth Development Office, within Covid-19 Therapeutics Accelerator partnership Wellcome, Bill Melinda Gates Foundation, Mastercard.

Language: Английский

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In silico prediction of potential inhibitors for SARS-CoV-2 Omicron variant using molecular docking and dynamics simulation-based drug repurposing

Journal of Molecular Modeling, Journal Year: 2023, Volume and Issue: 29(3)

Published: Feb. 20, 2023

Abstract Background In November 2021, variant B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the World Health Organization (WHO) and designated Omicron. Omicron is characterized a high number mutations, thirty-two in total, making it more transmissible than original virus. More half those mutations were found receptor-binding domain (RBD) that directly interacts with human angiotensin-converting enzyme (ACE2). This study aimed to discover potent drugs against Omicron, which previously repurposed for disease 2019 (COVID-19). All anti-COVID-19 compiled from previous studies tested RBD SARS-CoV-2 Methods As preliminary step, molecular docking performed investigate potency seventy-one compounds four classes inhibitors. The characteristics best-performing five predicted estimating drug-likeness drug score. Molecular dynamics simulations (MD) over 100 ns inspect relative stability best compound within site. Results current findings point out crucial roles Q493R, G496S, Q498R, N501Y, Y505H region Raltegravir, hesperidin, pyronaridine, difloxacin achieved highest scores compared other classes, values 81%, 57%, 18%, 71%, respectively. calculated results showed raltegravir hesperidin had binding affinities stabilities Δ G − 75.7304 ± 0.98324 42.693536 0.979056 kJ/mol, Further clinical should be two this study. Graphical

Language: Английский

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Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice

ACS Omega, Journal Year: 2022, Volume and Issue: 7(36), P. 31935 - 31944

Published: Aug. 29, 2022

The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency (dexamethasone, baricitinib, paxlovid, and molnupiravir), or in advanced clinical trials. Vandetanib kinase inhibitor which targets the vascular endothelial growth factor receptor (VEGFR), epidermal (EGFR), as well RET-tyrosine kinase. In current study, it was tested different cell lines showed promising results on inhibition versus toxic effect A549-hACE2 cells (IC

Language: Английский

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SARS-CoV-2 papain-like protease (PLpro) inhibitory and antiviral activity of small molecule derivatives for drug leads

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2023, Volume and Issue: 96, P. 129489 - 129489

Published: Sept. 27, 2023

Language: Английский

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Identification of SARS-CoV-2 Main Protease Inhibitors Using Chemical Similarity Analysis Combined with Machine Learning

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(2), P. 240 - 240

Published: Feb. 12, 2024

SARS-CoV-2 Main Protease (Mpro) is an enzyme that cleaves viral polyproteins translated from the genome, which critical for replication. Mpro a target anti-SARS-CoV-2 drug development. Herein, we performed large-scale virtual screening by comparing multiple structural descriptors of reference molecules with reported anti-coronavirus activity against library >17 million compounds. Further filtering, applying two machine learning algorithms, identified eighteen computational hits as compounds high diversity and drug-like properties. The activities twelve on Mpro’s enzymatic were evaluated fluorescence resonance energy transfer (FRET) assays. Compound 13 (ZINC13878776) significantly inhibited was employed experimentally hit expansion. analogues 13a (ZINC4248385), 13b (ZNC13523222), 13c (ZINC4248365) tested inhibitors, reducing recombinant potency follows: > 13a. Then, their in plaque reduction assays using Vero CCL81 cells. Subtoxic concentrations 13a, 13c, displayed vitro antiviral IC50 mid micromolar range. Compounds 13a–c could become lead development new inhibitors improved anti-SARS-CoV-2.

Language: Английский

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PBPK‐led assessment of antimalarial drugs as candidates for Covid‐19: Simulating concentrations at the site of action to inform repurposing strategies

Clinical and Translational Science, Journal Year: 2024, Volume and Issue: 17(7)

Published: July 1, 2024

Abstract The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID‐19) prompted a global effort evaluate repurposing opportunities. Pyronaridine amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome 2 (SARS‐CoV‐2). In does not always translate clinical efficacy across therapeutic dose range. This study applied available, verified, physiologically based pharmacokinetic (PBPK) models pyronaridine, amodiaquine, its active metabolite N‐desethylamodiaquine (DEAQ) predict concentrations lung tissue relative plasma or blood the default healthy virtual population. Lung exposures were compared published data reported range EC 50 values SARS‐CoV‐2. multicompartment permeability‐limited PBPK model, predicted total C max mass pyronaridine was 34.2 μM on Day 3, 30.5‐fold greater than (1.12 μM) 0.530 μM, 8.83‐fold (0.060 μM). perfusion‐limited DEAQ 3 (30.2 21.4‐fold (1.41 Based available data, DEAQ, but appeared sufficient inhibit SARS‐CoV‐2 replication. Simulations indicated standard dosing regimens pyronaridine‐artesunate artesunate‐amodiaquine have potential COVID‐19. These findings informed strategies select most relevant compounds investigation Clinical model verification may become from ongoing studies.

Language: Английский

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