The Chiral 5,6-Cyclohexane-fused Uracil Ring-System: a Molecular Platform with Promising Activity against SARS-CoV-2

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 286, P. 117302 - 117302

Published: Jan. 21, 2025

Language: Английский

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New perspective of small-molecule antiviral drugs development for RNA viruses

Virology, Journal Year: 2024, Volume and Issue: 594, P. 110042 - 110042

Published: March 7, 2024

Language: Английский

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Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (M^pro)

ACS Omega, Journal Year: 2024, Volume and Issue: 9(32), P. 34196 - 34219

Published: Aug. 2, 2024

Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), by SARS-CoV-2 its variants, further highlighted urgent need for development effective therapeutic agents. Currently, highly conserved broad-spectrum nature main proteases (M

Language: Английский

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Recent Advancements in the Therapeutic Development for Marburg Virus: Updates on Clinical Trials

Current Infectious Disease Reports, Journal Year: 2024, Volume and Issue: 26(2), P. 57 - 67

Published: Jan. 15, 2024

Language: Английский

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Development of Fluorescence-Based Assays for Key Viral Proteins in the SARS-CoV-2 Infection Process and Lifecycle

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2850 - 2850

Published: March 1, 2024

Since the appearance of SARS-CoV-2 in 2019, ensuing COVID-19 (Corona Virus Disease 2019) pandemic has posed a significant threat to global public health system, human health, life, and economic well-being. Researchers worldwide have devoted considerable efforts curb its spread development. The latest studies identified five viral proteins, spike protein (Spike), main protease (3CLpro), papain-like (PLpro), RNA-dependent RNA polymerase (RdRp), helicase (Helicase), which play crucial roles invasion into body lifecycle. development novel anti-SARS-CoV-2 drugs targeting these proteins holds immense promise. Therefore, efficient, high-throughput screening methodologies specifically designed for is utmost importance. Currently, plethora techniques exists, with fluorescence-based assays emerging as predominant contenders. In this review, we elucidate foundational principles underpinning approaches directed at pivotal targets, hoping guide researchers judicious selection refinement strategies, thereby facilitating discovery lead compounds pharmaceuticals.

Language: Английский

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Innovative Molecularly Imprinted Electrochemical Sensor for Selective Nanomolar Detection of the Anti-COVID-19 Medication Molnupiravir

Journal of The Electrochemical Society, Journal Year: 2024, Volume and Issue: 171(6), P. 067507 - 067507

Published: June 3, 2024

For the first time, a green ecofriendly approach is applied, to develop molecularly imprinted polymer (MIP) electrochemical for assay of oral anti-viral molnupiravir (MLN) in various matrices as confirmed by referring analytical eco-scale, procedure index (GAPI), Raynie and Driver, greenness metric (AGREE), national environmental (NEMI). AuNPs were chronoamperometry deposited on glassy carbon electrode surface (GCE) using 0.01 gm ml −1 gold solution (HAuCl 4 .3H 2 O) 0.5 M H SO at constant potential −0.4 V 60 s. Then, MIP was created electropolymerizing O PDA GCE cyclic voltammetry range between −0.5 +1 15 cycles (scan rate: 50 mV.s ). To optimize sensor’s performance, factors such number electropolymerization cycles, template: monomer ratio, binding rebinding pH buffer, extraction solvent, deposition time Au nanoparticles, order electrode; surface, well differential pulse parameters including accumulation step, all investigated. The detection limit set 0.00098 ng (3 × 10 −12 M) linearity MLN 0.033 164 (1 −10 –5 −7 M). sensor employed determination its pharmaceutical product (capsules), spiked human plasma, urine samples with mean recovery % ± relative standard deviation (RSD) (99.82% 0.53), (99.88% 0.62), (97.90% 0.70), respectively. investigated provided good reproducibility, repeatability, durability. Acceptable selectivity regarding when mixed structurally comparable compounds proved RSD (97.10% 0.03). Additionally, exposed oxidative, hydrolytic, thermal stress conditions, results stability-indicating studies served an indicator selectivity. developed coupled portable potentiostat, making it promising point-of-care diagnostic platform on-site measurements.

Language: Английский

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Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2

RSC Advances, Journal Year: 2023, Volume and Issue: 13(50), P. 35500 - 35524

Published: Jan. 1, 2023

The pandemic caused by the coronavirus SARS-CoV-2 led to a global crisis in world healthcare system. Despite some progress creation of antiviral vaccines and mass vaccination population, number patients continues grow because spread new mutations. There is an urgent need for direct-acting drugs capable suppressing or stopping main mechanisms reproduction SARS-CoV-2. Several studies have shown that successful replication virus cell requires proteolytic cleavage protein structures virus. Two proteases are crucial replicating other coronaviruses: protease (Mpro) papain-like (PLpro). In this review, we summarize essential viral proteins required its life cycle as targets chemotherapy infection provide critical summary development against COVID-19 from drug repurposing strategy up molecular design novel covalent non-covalent agents inhibiting replication. We overview choice Mpro PLpro promising pharmacological impact on cycle.

Language: Английский

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Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

The COVID-19 pandemic, exacerbated by persistent viral mutations, underscored the urgent need for diverse inhibitors targeting multiple proteins. In this study, we utilized covalent DNA-encoded libraries to discover innovative triazine-based 3-chymotrypsin-like protease (3CLpro, Nsp5) and papain-like (PLpro) domains of Nsp3, as well novel non-nucleoside nonstructural protein 12 (Nsp12, RdRp). Optimization through molecular docking medicinal chemistry led development LU9, a nonpeptide 3CLpro inhibitor with an IC50 0.34 μM, LU10, whose crystal structure showed distinct binding mode within active site. X-ray cocrystal SARS-CoV-2 PLpro in complex XD5 uncovered previously unexplored site adjacent catalytic pocket. Additionally, Nsp12 XJ5 achieved potency 0.12 μM following comprehensive structure–activity relationship analysis optimization. Molecular dynamics revealed potential mode. These compounds offer valuable chemical probes target validation represent promising candidates antiviral therapies.

Language: Английский

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De Novo Potent Peptide Nucleic Acid Antisense Oligomer Inhibitors Targeting SARS-CoV-2 RNA-Dependent RNA Polymerase via Structure-Guided Drug Design

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(24), P. 17473 - 17473

Published: Dec. 14, 2023

Global reports of novel SARS-CoV-2 variants and recurrence cases continue despite substantial vaccination campaigns, raising severe concerns about COVID-19. While repurposed drugs offer some treatment options for COVID-19, notably, nucleoside inhibitors like Remdesivir stand out as curative therapies COVID-19 that are approved by the US Food Drug Administration (FDA). The emergence highly contagious underscores imperative antiviral adaptable to evolving viral mutations. RNA-dependent RNA polymerase (RdRp) plays a key role in genome replication. Currently, inhibiting RdRp function remains pivotal strategy tackle notorious virus. Peptide nucleic acid (PNA) therapy shows promise effectively targeting specific regions, reducing replication, infection. In our study, we designed PNA antisense oligomers conjugated with cell-penetrating peptides (CPP) aiming evaluate their effects against target using structure-guided drug design, which involves molecular docking simulations, likeliness pharmacokinetic evaluations, dynamics computing binding free energy. silico analysis predicts chemically modified PNAs might act molecules order disrupt ribosome assembly at RdRp's translation start site, stable neutral backbone enhance sequence-specific interaction. Notably, findings demonstrate PNA-peptide conjugates be most promising RdRp, superior energy compared current medication. Specifically, PNA-CPP-1 could bind simultaneously active site residues protein RdRp-RNA control

Language: Английский

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Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain

BioMedInformatics, Journal Year: 2023, Volume and Issue: 3(4), P. 885 - 907

Published: Oct. 10, 2023

We hypothesize that in silico structural biology approaches can discover novel drug binding sites for RNA-dependent-RNA-polymerases (RdRp) of positive sense single-strand RNA (ss(+)RNA) virus species. RdRps have a structurally conserved active site with seven motifs (A to G), despite low sequence similarity. refined this architecture further describe domain consisting A, B, C and F. These were used realign 24 RdRp structures an innovative manner search sites. The aligned from the enzymes then docked 833 FDA-approved drugs (Set 1) 85 antivirals 2) using Molecular Operating Environment (MOE) docking 2020.09 software. Sirolimus (rapamycin), immunosuppressant targets mammalian mTOR pathway, was one top ten all proteins. sirolimus nucleotide triphosphate entry tunnel between A F but distinct motif C. This original finding supports our hypothesis based on are across evolution define new locations infer potential broad-spectrum inhibitors SARS-CoV-2 other ss(+)RNA viruses.

Language: Английский

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