Antiviral PROTACs: Opportunity borne with challenge

Cell Insight, Journal Year: 2023, Volume and Issue: 2(3), P. 100092 - 100092

Published: March 27, 2023

Proteolysis targeting chimera (PROTAC) degradation of pathogenic proteins by hijacking the ubiquitin-proteasome-system has become a promising strategy in drug design. The overwhelming advantages PROTAC technology have ensured rapid and wide usage, multiple PROTACs entered clinical trials. Several antiviral been developed with bioactivities against various viruses. However, number reported is far less than that other diseases, e.g., cancers, immune disorders, neurodegenerative possibly because common deficiencies (e.g., limited available ligands poor membrane permeability) plus complex mechanism involved high tendency viral mutation during transmission replication, which may challenge successful development effective PROTACs. This review highlights important advances this rapidly growing field critical limitations encountered developing analyzing current status representative examples PROTAC-like agents. We also summarize analyze general principles strategies for design optimization intent indicating potential strategic directions future progress.

Language: Английский

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Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 268, P. 116202 - 116202

Published: Feb. 6, 2024

To date, Proteolysis Targeting Chimera (PROTAC) technology has been successfully applied to mediate proteasomal-induced degradation of several pharmaceutical targets mainly related oncology, immune disorders, and neurodegenerative diseases. On the other hand, its exploitation in field antiviral drug discovery is still infancy. Recently, we described two indomethacin (INM)-based PROTACs displaying broad-spectrum activity against coronaviruses. Here, report design, synthesis, characterization a novel series INM-based that recruit either Von-Hippel Lindau (VHL) or cereblon (CRBN) E3 ligases. The panel was also enlarged by varying linker moiety. resulted very susceptible this modification, particularly for hijacking VHL as ligase, with one piperazine-based compound (PROTAC 6) showing potent anti-SARS-CoV-2 infected human lung cells. Interestingly, assays both uninfected virus-infected cells most promising emerged so far (PROTACs 5 demonstrated INM-PROTACs do not degrade PGES-2 protein, initially hypothesized, but induce concentration-dependent SARS-CoV-2 main protease (Mpro) Mpro-transfected SARS-CoV-2-infected Importantly, thanks target degradation, exhibited considerable enhancement respect indomethacin, EC50 values low-micromolar/nanomolar range. Finally, kinetic solubility well metabolic chemical stability were measured 6. Altogether, identification first class Mpro degraders demonstrating represents significant advance development effective, anti-coronavirus strategies.

Language: Английский

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Antiviral activity of Scutellaria baicalensis Georgi Extract against Getah virus in vivo and in vitro

Frontiers in Veterinary Science, Journal Year: 2025, Volume and Issue: 12

Published: March 25, 2025

Introduction The Getah virus (GETV) is a zoonotic arbovirus causing disease in humans and animals, member of the Alphavirus genus. Currently, approved antiviral drugs vaccines against alphaviruses are few available. This study aimed to investigate anti-GETV activity Extract Scutellaria baicalensis Georgi (ESG) vivo vitro . Methods cytotoxic effects ESG on BHK-21 cells were quantitatively evaluated through MTT assay. Quantitative analysis viral replication was performed using qRT-PCR, while E2 protein expression analyzed western blotting. Furthermore, molecular docking simulations conducted examine binding affinity between principal bioactive constituents structural proteins. Additionally, therapeutic potential alleviating viremia GETV-infected mouse models. Results results showed that significantly attenuated cytopathic induced by GETV infection cells, concurrently reducing both expression. Notably, exhibited its most potent during attachment entry phases, with IC50 values 3.69 μg/mL 3.94 μg/mL, respectively. At concentration 10 achieved 95.08% inhibition efficiency attachment. studies revealed treatment reduced peak load shortened duration mice. main components baicalin baicalein, demonstrated strong affinities these compounds active site protein, scores −6.99 kcal/mol for −5.21 baicalein. Conclusion experimental findings demonstrate exhibits significant efficacy These indicate represents promising candidate prevention infections. Mechanistically, appears be mediated, at least part, modulation

Language: Английский

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In silico screening of lactic acid bacteria methanolic extract for potential antiviral activity against Japanese encephalitis virus

Results in Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 102318 - 102318

Published: May 1, 2025

Language: Английский

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Aminoquinolines: Fluorescent sensors to DNA – A minor groove probe. Experimental and in silico studies

Journal of Photochemistry and Photobiology A Chemistry, Journal Year: 2023, Volume and Issue: 444, P. 114944 - 114944

Published: June 16, 2023

Language: Английский

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Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(21), P. 15518 - 15518

Published: Oct. 24, 2023

The COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly search candidates that interact with various SARS-CoV-2 receptors. These involve use of computer simulations and computational algorithms predict potential interaction target primary receptors targeted by include RNA polymerase, main protease, spike protein, ACE2 receptor, transmembrane protease serine 2 (TMPRSS2). identified several promising candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, Camostat Mesylate, among others. offers advantages, ability screen large number relatively short amount time, thereby reducing time cost involved traditional methods. Additionally, allow prediction binding affinity receptors, providing insight into their efficacy. This study is aimed at assessing useful contributions application instruments It further highlights some advantages limitations these studies, revealing complementary experimental validation ensure efficacy safety candidates.

Language: Английский

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In silico identification of chikungunya virus replication inhibitor validated using biochemical and cell‐based approaches

FEBS Journal, Journal Year: 2024, Volume and Issue: 291(12), P. 2656 - 2673

Published: Feb. 1, 2024

Discovering an alternative therapy with a long‐lasting effect on symptoms caused by chikungunya virus (CHIKV) infection is prompted the lack of vaccine and absence safe, effective non‐toxic medications. One potential strategy synthesizing or identifying small compounds that can specifically target active site essential enzyme prevent replication. Previous site‐directed mutagenesis studies have demonstrated crucial role macrodomain, which part non‐structural protein 3 (nsP3), in Exploiting this fact, macrodomain be targeted to discover natural substance inhibit its function thereby impede With aim, present study focused CHIKV nsP3 (nsP3 MD ) inhibitors through silico , vitro cell‐based methods. Through virtual screening compound library, nine were initially identified. Molecular dynamics (MD) simulations employed evaluate these based stability their ligand–receptor complexes energy parameters. Target analysis ADMET (i.e. absorption, distribution, metabolism, excretion toxicity) prediction selected revealed drug‐like characteristics. Subsequent investigation allowed us narrow selection down one compound, N ‐[2‐(5‐methoxy‐1H‐indol‐3‐yl) ethyl]‐2‐oxo‐1,2‐dihydroquinoline‐4‐carboxamide, exhibited potent inhibition growth. This molecule effectively inhibited replication stable embryonal rhabdomyosarcoma cell line capable producing CHIKV. Our findings demonstrate possesses substantial anti‐CHIKV activity both vivo . work provides promising for further preclinical develop drug against

Language: Английский

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PROTAC Beyond Cancer- Exploring the New Therapeutic Potential o f Proteolysis Targeting Chimeras

Current Topics in Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 24(23), P. 2050 - 2073

Published: July 4, 2024

In the realm of oncology, transformative impact PROTAC (PROteolysis TAgeting Chimeras) technology has been particularly pronounced since its introduction in 21st century. Initially conceived for cancer treatment, PROTACs have evolved beyond their primary scope, attracting increasing interest addressing a diverse array medical conditions. This expanded focus includes not only oncological disorders but also viral infections, bacterial ailments, immune dysregulation, neurodegenerative conditions, and metabolic disorders. comprehensive review explores broadening landscape application, highlighting ongoing developments innovations aimed at deploying these molecules across spectrum diseases. Careful consideration design challenges associated with reveals that, when appropriately addressed, compounds present significant advantages over traditional therapeutic approaches, positioning them as promising alternatives. To evaluate efficacy molecules, assays is employed, ranging from High-Throughput Imaging (HTI) to Cell Painting assays, CRBN engagement Fluorescence Polarization amplified luminescent proximity homogeneous Timeresolved fluorescence energy transfer Isothermal Titration Calorimetry assays. These assessments collectively contribute nuanced understanding performance. Looking ahead, trajectory suggests potential recognition versatile strategy an expansive range Ongoing progress this field sets stage emerge valuable tools multifaceted treatments.

Language: Английский

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Early Multi-Target Treatment of Mild-to-Moderate COVID-19, Particularly in Terms of Non-Steroidal Anti-Inflammatory Drugs and Indomethacin

BioMed, Journal Year: 2023, Volume and Issue: 3(1), P. 177 - 194

Published: March 10, 2023

Recently, in Italy, a flowchart to be used by General Practitioners for the at-home treatment of patients with COVID-19, has been released. It states that early SARS-CoV-2 infection is possible due availability specific antiviral drugs at-risk patients, and non-steroidal anti-inflammatory (NSAIDs) have an important function combating virus. Therefore, use NSAIDs not only rational but also effective cases cannot treated using antivirals. These seemingly simple concepts applied Italy since beginning pandemic doctors belong Italian groups created order help COVID-19 at home, time organizational difficulties within health institutions government. However, this approach was largely boycotted both Ministry Health medical institutions, which mainly suggested paracetamol as symptomatic, wait-and-watch first three days from onset symptoms. In article, we analyze rationale and, particular, multi-targeted including indomethacin synergism flavonoids low-dose aspirin, COVID-19. Applying these could reduced high lethality disease during two years prevented hospital overload. perspective, it still necessary systematically address comparison between different therapeutic approaches viral on experimental basis.

Language: Английский

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Phytochemicals of Different Medicinal Herbs as Potential Inhibitors Against Dengue Serotype 2 Virus: A Computational Approach

Molecular Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 12, 2024

Language: Английский

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