Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 13, 2025

The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents systematic design quinoline-containing papain-like protease (PLpro) inhibitors as potential antiviral drug candidates. By leveraging recently discovered Val70Ub binding site in PLpro, we designed a series quinoline analogs demonstrating potent PLpro inhibition and activity. Notably, X-ray crystal structures 6 lead compounds reveal that 2-aryl substitution can occupy either expected or BL2 groove flipped orientation. vivo Jun13296 exhibits favorable pharmacokinetic properties against nirmatrelvir-resistant mutants. In mouse model infection, treatment with significantly improves survival, reduces body weight loss lung viral titers, prevents tissue damage. These results underscore promising candidates, instilling hope for future treatment. inhibitor, Jun13296, displays efficacy infection inhibits mutants, rendering it candidate.

Язык: Английский

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Preclinical and Clinical Investigations of Potential Drugs and Vaccines for COVID-19 Therapy: A Comprehensive Review With Recent Update

Clinical Pathology, Год журнала: 2024, Номер 17

Опубликована: Янв. 1, 2024

The COVID-19 pandemic-led worldwide healthcare crisis necessitates prompt societal, ecological, and medical efforts to stop or reduce the rising number of fatalities. Numerous mRNA based vaccines for viral vectors have been licensed use in emergencies which showed 90% 95% efficacy preventing SARS-CoV-2 infection. However, safety issues, vaccine reluctance, skepticism remain major concerns making mass vaccination a successful approach treat COVID-19. Hence, alternative therapeutics is needed eradicating global burden from developed low-resource countries. Repurposing current medications drug candidates could be more viable option treating as these therapies previously passed significant checkpoints development patient care. Besides vaccines, this review focused on potential usage therapeutic agents including antiviral, antiparasitic, antibacterial drugs, protease inhibitors, neuraminidase monoclonal antibodies that are currently undergoing preclinical clinical investigations assess their effectiveness treatment Among repurposed remdesivir considered most promising agent, while favipiravir, molnupiravir, paxlovid, lopinavir/ritonavir exhibited improved effects terms elimination viruses. outcomes with oseltamivir, umifenovir, disulfiram, teicoplanin, ivermectin were not significant. It noteworthy combining multiple drugs therapy showcases impressive managing individuals Tocilizumab presently employed patients who exhibit COVID-19-related pneumonia. antiviral such galidesivir, griffithsin, thapsigargin under trials severe symptoms. Supportive may involve corticosteroids, convalescent plasma, stem cells, pooled antibodies, vitamins, natural substances. This study provides an updated progress crucial guide inventing novel interventions against

Язык: Английский

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Perturbation of de novo lipogenesis hinders MERS-CoV assembly and release, but not the biogenesis of viral replication organelles

Journal of Virology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

ABSTRACT Coronaviruses hijack host cell metabolic pathways and resources to support their replication. They induce extensive endomembrane remodeling generate viral replication organelles exploit membranes for assembly budding of enveloped progeny virions. Because the overall significance membranes, we sought gain insight into role factors involved in lipid metabolism cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV). We employed a single-cycle infection approach combination pharmacological inhibitors, biochemical assays, lipidomics, light electron microscopy. Pharmacological inhibition acetyl-CoA carboxylase (ACC) fatty acid synthase (FASN), key de novo biosynthesis, led pronounced MERS-CoV particle release. Inhibition ACC profound switch Huh7 cells, altering lipidomic profile inducing lipolysis. However, despite changes induced by inhibitor, biogenesis remained unaffected. Instead, appeared affect trafficking post-translational modifications envelope proteins. Electron microscopy revealed an accumulation nucleocapsids early stages, indicating that is adversely impacted inhibition. Notably, palmitoylation resulted similar effects, while supplementation exogenous palmitic reversed compound’s inhibitory possibly reflecting crucial need spike proteins virus assembly. IMPORTANCE (MERS-CoV) etiological agent zoonotic disease limited transmissibility between humans. still considered high-priority pathogen closely monitored WHO due its high lethality rate around 35% laboratory-confirmed infections. Like other positive-strand RNA viruses, relies on cell’s endomembranes various stages cycle. spite this general reliance metabolism, mechanistic insights are very limited. In our study, show (ACC), enzyme biosynthesis pathway, significantly disrupts without exerting negative effect organelles. Furthermore, study highlights potential as target development host-directed antiviral therapeutics against coronaviruses.

Язык: Английский

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From Plasmid to Pure Protein: Production and Characterization of SARS-CoV-2 PL^pro

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 11, 2025

Summary Papain-like protease (PL pro ) from SARS-CoV-2 is a high-priority target for COVID-19 antiviral drug development. We present protocols PL production in Escherichia coli . expressed as fusion with the Saccharomyces cerevisiae Smt3 protein (SUMO), purified and obtained its native form upon hydrolysis, yields high 38 mg L -1 The protocol also provides isotope-enriched samples suitable NMR studies. Protocols are presented characterization by mass spectrometry, 1D 19 F-NMR 2D heteronuclear NMR, fluorescence-based enzyme assay. Highlights Production, purification, biochemical analysis of N- C-termini High E. , up to using lysogeny broth. Supports labeled inhibitor interaction F fluorescence assays screening IC 50 determination. eTOC Blurb key cysteine involved viral replication immune evasion, making it an important This study presents detailed production, analysis, achieving workflow includes expression His-SUMO tag, isotope labeling studies, quantifying inhibitors. comprehensive guide facilitates large-scale active discovery structural

Язык: Английский

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Evaluation in Silico of the (Pbthtx-I)2k Peptide as a Sars-Cov-2 Plpro Protease Inhibitor

Опубликована: Янв. 1, 2025

Download This Paper Open PDF in Browser Add to My Library Share: Permalink Using these links will ensure access this page indefinitely Copy URL DOI

Язык: Английский

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Dose and strain dependent lethality of Usutu virus in an Ifnar−/− mouse model

npj Viruses, Год журнала: 2025, Номер 3(1)

Опубликована: Янв. 28, 2025

Abstract Usutu virus (USUV) is a mosquito-borne zoonotic flavivirus with geographic range that has expanded over recent years. Maintained in transmission cycle between mosquito vectors and avian reservoirs the can cause large seasonal outbreaks bird populations, but spillover into mammalian hosts also been reported. While usually mild or asymptomatic humans, neurological disorders are increasingly observed, which boosted interest need for better understanding of pathogenesis various USUV lineages. In this study we inoculated interferon α/β receptor knockout (Ifnar −/− ) mice decreasing doses USUV, monitoring symptoms survival to determine less lethal dose, directly compared isolates from three different viral We found Dutch isolate Africa-3 lineage at dose 20 pfu per mouse, considerably lower than what was anticipated based upon literature. A Europe-2 strain showed an even higher virulence mouse model, strains Europe-3 lineages—though not reflected vitro studies. These results enhance our pathogenicity provide guidance use low inoculation Ifnar animal model.

Язык: Английский

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Mechanistic Insights into Targeting SARS-CoV-2 Papain-like Protease in the Evolution and Management of COVID-19

BioChem, Год журнала: 2024, Номер 4(3), С. 268 - 299

Опубликована: Сен. 23, 2024

The COVID-19 pandemic, instigated by the emergence of novel coronavirus, SARS-CoV-2, created an incomparable global health crisis. Due to its highly virulent nature, identifying potential therapeutic agents against this lethal virus is crucial. PLpro a key protein involved in viral polyprotein processing and immune system evasion, making it prime target for development antiviral drugs combat COVID-19. To expedite search candidates, review delved into computational studies. Recent investigations have harnessed methods identify promising inhibitors targeting PLpro, aiming suppress activity. Molecular docking techniques were employed researchers explore binding sites within catalytic region PLpro. elucidates functional structural properties SARS-CoV-2 underscoring significance pathogenicity replication. Through comprehensive all-atom molecular dynamics (MD) simulations, stability drug–PLpro complexes was assessed, providing dynamic insights their interactions. By evaluating energy estimates from MD stable with identified. This offers overview drug/lead candidates discovered thus far using diverse silico methodologies, encompassing drug repurposing, structure-based, ligand-based virtual screenings. Additionally, identified are listed based on chemical structures meticulously examined according various parameters, such as estimated free (ΔG), types intermolecular interactions, PLpro–ligand complexes, determined outcomes simulations. Underscoring pivotal role battle COVID-19, establishes robust foundation integrating modeling, insights. continual imperative improvement existing exploring compounds remains paramount efforts evolution management hinge symbiotic relationship between experimental validation, interdisciplinary synergy crucial endeavor.

Язык: Английский

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Arylamines QSAR-Based Design and Molecular Dynamics of New Phenylthiophene and Benzimidazole Derivatives with Affinity for the C111, Y268, and H73 Sites of SARS-CoV-2 PLpro Enzyme

Pharmaceuticals, Год журнала: 2024, Номер 17(5), С. 606 - 606

Опубликована: Май 9, 2024

A non-structural SARS-CoV-2 protein, PLpro, is involved in post-translational modifications cells, allowing the evasion of antiviral immune response mechanisms. In this study, potential PLpro inhibitory drugs were designed using QSAR, molecular docking, and dynamics. combined QSAR equation with physicochemical Free-Wilson descriptors was formulated. The r2, q2, r2test values 0.833, 0.770, 0.721, respectively. From equation, it found that presence an aromatic ring a basic nitrogen atom crucial for obtaining good activity. Then, series structures binding sites C111, Y268, H73 created. best compounds to exhibit pIC50 9.124 docking scoring -14 kcal/mol. stability cavities confirmed by dynamics studies. high number stable contacts interactions over time exhibited aryl-thiophenes Pred14 Pred15, making them candidates.

Язык: Английский

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Perturbation of de novo lipogenesis hinders MERS-CoV assembly and release, but not the biogenesis of viral replication organelles

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 23, 2024

Abstract Coronaviruses hijack host cell metabolic pathways and resources to support their replication. They induce extensive endomembrane remodeling generate viral replication organelles, exploit membranes for assembly budding of enveloped progeny virions. Because the overall significance membranes, we sought gain insight into role factors involved in lipid metabolism cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV). We employed a single-cycle infection approach combination pharmacological inhibitors, biochemical assays, lipidomics, light electron microscopy. Pharmacological inhibition acetyl-CoA carboxylase (ACC) fatty acid synthase (FASN), key de novo biosynthesis, led pronounced MERS-CoV particle release. Inhibition ACC profound switch Huh7 cells, altering lipidomic profile inducing lipolysis. However, despite changes induced by inhibitor, biogenesis organelles remained unaffected. Moreover, compound treatment triggered various simultaneous post-translational modifications envelope proteins, addition influencing subcellular localization. Electron microscopy revealed an accumulation nucleocapsids early stages, indicating that is adversely impacted inhibition. Notably, palmitoylation resulted similar effects, while supplementation exogenous palmitic reversed compound’s inhibitory possibly reflecting crucial need Spike Envelope proteins virus assembly. Importance respiratoryspiratory (MERS-CoV) etiological agent zoonotic disease limited transmissibility between humans. still considered high-priority pathogen closely monitored WHO due its high lethality rate around 35% laboratory-confirmed infections. Like other positive-strand RNA viruses, relies on cell’s endomembranes stages cycle. spite this general reliance metabolism, mechanistic insights are very limited. In our study, show (ACC), enzyme biosynthesis pathway, significantly disrupts without exerting negative effect organelles. Furthermore, study highlights potential as target development host-directed antiviral therapeutics against coronaviruses.

Язык: Английский

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Identification of Novel Allosteric Sites of SARS-CoV-2 Papain-Like Protease (PLpro) for the Development of COVID-19 Antivirals

Journal of Biological Chemistry, Год журнала: 2024, Номер unknown, С. 107821 - 107821

Опубликована: Сен. 1, 2024

Язык: Английский

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