Natural triterpenoids from licorice potently inhibit SARS-CoV-2 infection

Journal of Advanced Research, Journal Year: 2021, Volume and Issue: 36, P. 201 - 210

Published: Nov. 26, 2021

The COVID-19 global epidemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a great public health emergency. Discovering antiviral drug candidates urgent for the prevention and treatment of COVID-19. This work aims to discover natural SARS-CoV-2 inhibitors from traditional Chinese herbal medicine licorice. We screened 125 small molecules Glycyrrhiza uralensis Fisch. (licorice, Gan-Cao) virtual ligand screening targeting receptor-binding domain (RBD) spike protein. Potential hit compounds were further evaluated ELISA, SPR, luciferase assay, assay pharmacokinetic study. triterpenoids licorice-saponin A3 (A3) glycyrrhetinic acid (GA) could potently inhibit infection, with EC50 75 nM 3.17 µM, respectively. Moreover, we reveal that mainly targets nsp7 protein, GA binds protein RBD SARS-CoV-2. In this work, found licorice infection affecting entry replication virus. Our findings indicate these may contribute clinical efficacy be promising development.

Language: Английский

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Nirmatrelvir plus ritonavir (Paxlovid) a potent SARS-CoV-2 3CLpro protease inhibitor combination

Revista Española de Quimioterapia, Journal Year: 2022, Volume and Issue: 35(3), P. 236 - 240

Published: Feb. 20, 2022

All coronavirus, including SARS-CoV-2, encode two proteases needed for the processing of PP1A and PP1AB polyproteins. The main protease 3CL (chemotripsine-like) gives rise to formation NSP11/16 proteins. has been constituted as one possible therapeutic targets development antiviral drugs against SARS-COV-2 due its highly conserved sequence structure among all coronaviruses. During SARS-COV-1 pandemic, a hydroxymethyl ketone derivative (PF-00835231) was identified with an intense inhibitory activity protease. Subsequent chemical modifications gave PF-07321332 (nirmatrelvir) which shown high efficacy SARS-COV-2. company's data indicate that it is capable reducing 89% risk hospitalization death patients infected hardly adverse effects. Its effectiveness improves if administered orally in first 24-48 hours duration treatment established between 3-5 days. commercial form associated ritonavir metabolism nirmatrelvir, lengthening average life. This would be effective current future viral variants, since not modified them. FDA approved this November 2021 EMA final evaluation phase.

Language: Английский

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Design and Evaluation of a Novel Peptide–Drug Conjugate Covalently Targeting SARS-CoV-2 Papain-like Protease

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(1), P. 876 - 884

Published: Jan. 4, 2022

Coronavirus disease 2019 (COVID-19) pandemic, a global health threat, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 papain-like cysteine protease (PLpro) recognized as promising drug target because of multiple functions in virus maturation and antiviral immune responses. Inhibitor GRL0617 occupied the interferon-stimulated gene 15 (ISG15) C-terminus-binding pocket showed an effective inhibition. Here, we described novel peptide-drug conjugate (PDC), which linked to sulfonium-tethered peptide derived from PLpro-specific substrate LRGG. EM-C EC-M PDCs vitro IC50 7.40 ± 0.37 8.63 0.55 μM, respectively. could covalently label PLpro active site C111 display anti-ISGylation activities cellular assays. results represent first attempt design composed stabilized inhibitors inhibit PLpro. These provide opportunities for design.

Language: Английский

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Molecular Interactions of Tannic Acid with Proteins Associated with SARS-CoV-2 Infectivity

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(5), P. 2643 - 2643

Published: Feb. 27, 2022

The overall impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on our society is unprecedented. identification small natural ligands that could prevent the entry and/or replication remains a pertinent approach to fight disease (COVID-19) pandemic. Previously, we showed phenolic compounds corilagin and 1,3,6-tri-O-galloyl-β-D-glucose (TGG) inhibit interaction between SARS-CoV-2 spike protein receptor binding domain (RBD) angiotensin-converting enzyme (ACE2), target cell membrane host organism. Building these promising results, now assess effects two other crucial targets involved in replication, respectively: transmembrane protease serine (TMPRSS2) 3-chymotrypsin like (3CLpro) inhibitors. Since corilagin, TGG, tannic acid (TA) share many physicochemical structural properties, investigate TA targets. In this work, combination experimental methods (biochemical inhibition assays, surface plasmon resonance, quartz crystal microbalance with dissipation monitoring) confirms potential role prevention infectivity through extracellular RBD/ACE2 interactions TMPRSS2 3CLpro activity. Moreover, molecular docking prediction followed by dynamic simulation mechanics Poisson-Boltzmann area (MMPBSA) free energy calculation also shows binds RBD, TMPRSS2, higher affinities than TGG corilagin. Overall, results suggest naturally occurring candidate SARS-CoV-2.

Language: Английский

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Therapeutic implications of quercetin and its derived-products in COVID-19 protection and prophylactic

Heliyon, Journal Year: 2024, Volume and Issue: 10(9), P. e30080 - e30080

Published: April 30, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel human coronavirus, which has triggered global pandemic of the infectious disease 2019 (COVID-19). Outbreaks emerging diseases continue to challenge health worldwide. The virus conquers cells through angiotensin-converting enzyme receptor-driven pathway by mostly targeting tract. Quercetin is natural flavonoid widely represented in plant kingdom. Cumulative evidence demonstrated that quercetin and its derivatives have various pharmacological properties including anti-cancer, anti-hypertension, anti-hyperlipidemia, anti-hyperglycemia, anti-microbial, antiviral, neuroprotective, cardio-protective effects, because it potential treatment for severe inflammation distress syndrome. Furthermore, main life-threatening condition patients with COVID-19. This article provides comprehensive review primary literature on predictable effectiveness docked multi-target SARS-CoV-2 host via

Language: Английский

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Computational Investigations for Identification of Bioactive Molecules from Baccaurea ramiflora and Bergenia ciliata as Inhibitors of SARS-CoV-2 M^pro

Polycyclic aromatic compounds, Journal Year: 2022, Volume and Issue: 43(3), P. 2459 - 2487

Published: March 6, 2022

In this study, a hybrid compound library of 72 phytocompounds from two antiviral medicinal plants (Baccaurea ramiflora and Bergenia ciliata) was computationally investigated for their inhibitory potential against SARS-CoV-2 Mpro. Molecular docking showed that 6-O-vanilloylicariside B5, 6-O-vanilloylisotachioside, leucoanthocyanidin 4-(2-galloyl), p-hydroxybenzoyl bergenin has good binding affinity However, did not bind at the catalytic cavity. The RMSD RMSF data obtained 100 ns MD simulations revealed stable protein–ligand complexes 4-(2-galloyl). Ligand trajectory study found 6-O-vanilloylisotachioside 4-(2-galloyl) to be stable. Studies on ligand interaction profile timeline interacted with HIS41–CYS145 dyad other crucial amino acids site cavity during entire simulations. mechanics generalized born solvent accessibility free energy calculations, density functional theory analysis, quantitative structure–property relationship studies, ADMET profiling supported results generated by molecular studies. Based current computational investigations, we conclude B. ciliata are inhibitors Mpro worthy further investigations.

Language: Английский

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Design and statistical optimisation of emulsomal nanoparticles for improved anti-SARS-CoV-2 activity of N -(5-nitrothiazol-2-yl)-carboxamido candidates: in vitro and in silico studies

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 38(1)

Published: April 24, 2023

In this article, emulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g) in an attempt improve their biological availability and antiviral activity. Next, both cytotoxicity anti-SARS-CoV-2 activities of examined compounds loaded EMLs (F3a-g) assessed Vero E6 cells via MTT assay calculate CC50 inhibitory concentration 50 (IC50) values. The most potent 3e-loaded (F3e) elicited a selectivity index 18 with IC50 value 0.73 μg/mL. Moreover, F3e was selected for further elucidation possible mode action where results showed that it exhibited combination virucidal (>90%), viral adsorption (>80%), replication (>60%) inhibition. Besides, molecular docking MD simulations towards SARS-CoV-2 Mpro performed. Finally, structure-activity relationship (SAR) study focussed on studying influence altering size, type, flexibility α-substituent carboxamide addition compound contraction activity.HighlightsEmulsomes (3a-3g).The μg/mL against SARS-CoV-2.F3e inhibition.Molecular docking, dynamics (MD) simulations, MM-GBSA calculations performed.Structure-activity discussed

Language: Английский

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Structure-Function Characteristics of SARS-CoV-2 Proteases and Their Potential Inhibitors from Microbial Sources

Microorganisms, Journal Year: 2021, Volume and Issue: 9(12), P. 2481 - 2481

Published: Nov. 30, 2021

The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is considered the greatest challenge to global health community of century as it continues expand. This has prompted immediate urgency discover promising drug targets for treatment COVID-19. SARS-CoV-2 viral proteases, 3-chymotrypsin-like protease (3CLpro) and papain-like cysteine (PLpro), have become target study due their essential functions in spreading virus RNA transcription, translation, protein synthesis, processing modification, replication, infection host. As such, understanding structure function these two proteases unavoidable platforms development inhibitors targeting this which further arrest spread virus. While abundance reports on screening natural compounds such are available, microorganisms-based (peptides non-peptides) remain less studied. Indeed, also one potent antiviral candidates against Microbes, especially bacteria fungi, other resources produce new drugs well nucleosides, nucleotides, nucleic acids. Thus, we compiled various reported literature detail structures, potential from microbial sources assistance researchers working with compared HIV suggested advantageous SARS-CoV2 inhibitors. information should serve a platform design strategies.

Language: Английский

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AI-Driven De Novo Design and Molecular Modeling for Discovery of Small-Molecule Compounds as Potential Drug Candidates Targeting SARS-CoV-2 Main Protease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(9), P. 8083 - 8083

Published: April 29, 2023

Over the past three years, significant progress has been made in development of novel promising drug candidates against COVID-19. However, SARS-CoV-2 mutations resulting emergence new viral strains that can be resistant to drugs used currently clinic necessitate potent and broad therapeutic agents targeting different vulnerable spots proteins. In this study, two deep learning generative models were developed combination with molecular modeling tools for de novo design small molecule compounds inhibit catalytic activity main protease (Mpro), an enzyme critically important mediating replication transcription. As a result, seven best scoring exhibited low values binding free energy comparable those calculated inhibitors Mpro, via same computational protocol, selected as most probable site. light data obtained, identified are assumed present scaffolds broad-spectrum inhibiting attractive target anti-COVID-19 agents.

Language: Английский

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Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS‐CoV‐2

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 14, 2023

The coronavirus disease 2019 (COVID-19) pandemic has affected a large portion of the global population, both physically and mentally. Current evidence suggests that rapidly evolving subvariants risk rendering vaccines antibodies ineffective due to their potential evade existing immunity, with enhanced transmission activity higher reinfection rates could lead new outbreaks across globe. goal viral management is disrupt life cycle as well relieve severe symptoms such lung damage, cytokine storm, organ failure. In fight against viruses, combination genome sequencing, elucidation structure proteins, identifying proteins are highly conserved multiple coronaviruses revealed many molecular targets. addition, time- cost-effective repurposing preexisting antiviral drugs or approved/clinical for these targets offers considerable clinical advantages COVID-19 patients. This review provides comprehensive overview various identified pathogenic pathways corresponding repurposed COVID-19. These findings provide insight into discovery novel therapeutic strategies be applied control emanating from SARS-CoV-2 variants.

Language: Английский

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