The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(2), P. 217 - 217

Published: Feb. 2, 2024

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms action some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. most effective drug approved date for treatment is PaxlovidTM, which combination two protease inhibitors, nirmatrelvir ritonavir. Nirmatrelvir reversible covalent peptidomimetic inhibitor main (Mpro) SARS-CoV-2, enzyme plays crucial role reproduction. In this combination, ritonavir serves as pharmacokinetic enhancer, it irreversibly inhibits cytochrome CYP3A4 responsible rapid metabolism nirmatrelvir, thereby increasing half-life bioavailability nirmatrelvir. tutorial review, we summarize development pharmaceutical chemistry aspects Paxlovid, covering evolution warhead design, synthesis mechanism well its inhibition mechanism. efficacy Paxlovid novel virus mutants also overviewed.

Language: Английский

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Genetic Predictors of Paxlovid Treatment Response: The Role of IFNAR2, OAS1, OAS3, and ACE2 in COVID-19 Clinical Course

Journal of Personalized Medicine, Journal Year: 2025, Volume and Issue: 15(4), P. 156 - 156

Published: April 17, 2025

Background: This study investigated the role of genetic polymorphisms in IFNAR2, OAS1, OAS3, and ACE2 as predictors Paxlovid treatment response, specifically examining their influence on clinical course laboratory parameters COVID-19 patients. Methods: We analyzed impact genes associated with interferon pathway (IFNAR2 rs2236757), antiviral response (OAS1 rs10774671, OAS3 rs10735079), viral entry (ACE2 rs2074192) individuals treated Paxlovid. Results: Our findings suggest that variations these may modulate immune coagulation pathways context during infection. Specifically, IFNAR2 rs2236757 G allele was alterations inflammatory markers, while OAS1 influenced parameters. Furthermore, specific genotypes were linked to changes such oxygen saturation, leukocyte count, liver function markers Paxlovid-treated Conclusions: These results highlight potential considering factors understanding individual responses informing future personalized approaches.

Language: Английский

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Recent Advances on SARS-CoV-2 Mpro Inhibitors: From Nirmatrelvir to Future Perspectives

Published: Aug. 2, 2023

The Main Protease (Mpro) plays a pivotal role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is considered highly conserved viral target. Disruption catalytic activity Mpro produces detrimental effect on course infection, making this target one most attractive for treatment COVID-19. current success SARS-CoV-2 inhibitor Nirmatrelvir, first oral drug forms COVID-19, has further focused attention researchers important target, search new inhibitors thriving exciting field development antiviral drugs active against related coronaviruses.

Language: Английский

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Exploring the Antiviral Potential of Esters of Cinnamic Acids with Quercetin

Viruses, Journal Year: 2024, Volume and Issue: 16(5), P. 665 - 665

Published: April 24, 2024

Severe acute respiratory syndrome-related Coronavirus 2 (SARS-CoV-2) has infected more than 762 million people to date and caused approximately 7 deaths all around the world, involving 187 countries. Although currently available vaccines show high efficacy in preventing severe complications patients, number of mutations S proteins current variants is responsible for level immune evasion transmissibility virus reduced effectiveness acquired immunity. In this scenario, development safe effective drugs synthetic or natural origin suppress viral replication treat forms COVID-19 remains a valid therapeutic challenge. Given successful history flavonoids-based drug discovery, we developed esters substituted cinnamic acids with quercetin evaluate their vitro activity against broad spectrum Coronaviruses. Interestingly, two derivatives, 3,4-methylenedioxy 6 ester acid 7, have proved be reducing OC43-induced cytopathogenicity, showing interesting EC50s profiles. The synaptic particular, which not endowed relevant cytotoxicity under any tested conditions, turned out active OC43 SARS-CoV-2, promising EC50. Therefore, said compound was selected as lead object further analysis. When yield reduction, assay produced significant dose-dependent reduction titer. However, virucidal, exposure concentrations it did affect infectivity, nor hCoV-OC43 penetration into pre-treated host cells. Additional studies on action mechanism suggested that our derivative may inhibit endocytosis by attachment

Language: Английский

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Targeting Viral and Cellular Cysteine Proteases for Treatment of New Variants of SARS-CoV-2

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 338 - 338

Published: Feb. 22, 2024

The continuous emergence of SARS-CoV-2 variants caused the persistence COVID-19 epidemic and challenged effectiveness existing vaccines. viral proteases are most attractive targets for developing antiviral drugs. In this scenario, our study explores use HIV-1 protease inhibitors against SARS-CoV-2. An in silico screening a library identified four anti-HIV compounds able to interact with 3CLpro Thus, vitro studies were designed evaluate their potential We employed pseudovirus technology simulate, highly safe manner, adsorption alpha (α-SARS-CoV-2) omicron (ο-SARS-CoV-2) inhibitory mechanism selected cell–virus interaction. results reported mild activity PLpro, but efficient effects on internalization both mediated by cathepsin B/L. Our findings provide insights into feasibility using drugs exhibiting other viruses host required entry.

Language: Английский

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Research Progress on the Structure and Function, Immune Escape Mechanism, Antiviral Drug Development Methods, and Clinical Use of SARS-CoV-2 Mpro

Molecules, Journal Year: 2025, Volume and Issue: 30(2), P. 351 - 351

Published: Jan. 16, 2025

The three-year COVID-19 pandemic ‘has’ caused a wide range of medical, social, political, and financial implications. Since the end 2020, various mutations variations in SARS-CoV-2 strains, along with immune escape phenomenon, have emerged. There is an urgent need to identify relatively stable target for development universal vaccines drugs that can effectively combat both strains their mutants. Currently, main focus treating lies disrupting virus’s life cycle. protease (Mpro) closely associated virus replication maturation plays crucial role early stages infection. Consequently, it has become important SARS-CoV-2-specific drugs. This review summarizes recent research progress on novel coronavirus’s proteases, including pivotal Mpro cycle, structure catalytic mechanism Mpro, self-maturation escape, current methods developing antiviral targeting key successfully entered clinical trials. aim provide researchers involved systematic comprehensive information.

Language: Английский

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Advances in Virus Biorecognition and Detection Techniques for the Surveillance and Prevention of Infectious Diseases

Biosensors, Journal Year: 2025, Volume and Issue: 15(3), P. 198 - 198

Published: March 20, 2025

Viral infectious diseases pose a serious threat to global public health due their high transmissibility, rapid mutation rates, and limited treatment options. Recent outbreaks of such as plague, monkeypox, avian influenza, coronavirus disease 2019 (COVID-19) have underscored the urgent need for efficient diagnostic surveillance technologies. Focusing on viral that seriously threaten human health, this review summarizes analyzes detection techniques from perspective combining prevention advice, discusses applications in improving sensitivity specificity. One major innovations is systematic integration advanced biorecognition technologies, bionanosensors, test strips, microfluidic platforms, along with exploration artificial intelligence virus detection. These technologies address limitations traditional methods enable real-time monitoring early warning outbreaks. By analyzing application these pathogens, new insights are provided development next-generation tools emerging re-emerging threats. In addition, we analyze current progress developed vaccines, vaccine research provide ideas future control development, call attention

Language: Английский

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Machine Learning-Guided Screening and Molecular Docking for Proposing Naturally Derived Drug Candidates Against MERS-CoV 3CL Protease

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3047 - 3047

Published: March 26, 2025

In this study, we utilized machine learning techniques to identify potential inhibitors of the MERS-CoV 3CL protease. Among models evaluated, Random Forest (RF) algorithm exhibited highest predictive performance, achieving an accuracy 0.97, ROC-AUC score 0.98, and F1-score 0.98. Following model validation, applied it a dataset 14,194 naturally occurring compounds from PubChem. The top-ranked were subsequently subjected molecular docking, which identified Perenniporide B, Phellifuropyranone A, Terrestrol G as most promising candidates, with binding energies -9.17, -9.08, -8.71 kcal/mol, respectively. These formed strong interactions key catalytic residues, suggesting significant inhibitory against viral Furthermore, dynamics simulations confirmed their stability within active site, reinforcing viability antiviral agents. This study demonstrates effectiveness integrating modeling accelerate discovery therapeutic candidates emerging threats.

Language: Английский

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Nirmatrelvir: From Discovery to Modern and Alternative Synthetic Approaches

Processes, Journal Year: 2024, Volume and Issue: 12(6), P. 1242 - 1242

Published: June 17, 2024

The global urgency in response to the COVID-19 pandemic has catalyzed extensive research into discovering efficacious antiviral compounds against SARS-CoV-2. Among these, Nirmatrelvir (PF-07321332) emerged as a promising candidate, exhibiting potent activity by targeting main protease of SARS-CoV-2, and been marketed combination with ritonavir first oral treatment for name PaxlovidTM. This review outlines synthetic approaches Nirmatrelvir, ranging from Pfizer’s original method newer, more sustainable strategies, such flow chemistry strategies multicomponent reactions. Each approach’s novelty contributions yield purification processes are highlighted. Additionally, synthesis key fragments comprising innovative optimization discussed.

Language: Английский

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An Integrated In Silico and In Vitro Approach for the Identification of Natural Products Active against SARS-CoV-2

Biomolecules, Journal Year: 2023, Volume and Issue: 14(1), P. 43 - 43

Published: Dec. 28, 2023

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has provoked a global health crisis due to the absence of specific therapeutic agent. 3CLpro (also known as main protease or Mpro) and PLpro are chymotrypsin-like proteases encoded SARS-CoV-2 genome, play essential roles during virus lifecycle. Therefore, they recognized prospective target in drug discovery against infection. Thus, this work aims collectively present potential natural inhibitors silico simulations vitro entry pseudotype-entry models. We screened luteolin-7-O-glucuronide (L7OG), cynarin (CY), folic acid (FA), rosmarinic (RA) molecules through luminogenic substrate assay. only reported moderate inhibitory activity on recombinant L7OG FA. Afterward, FA was tested cell lines transduced with two different pseudotypes harboring alpha (α) omicron (o) spike (S) protein. The results showed that both compounds have consistent for variants. However, greater degree inhibition α-SARS-CoV-2. Molecular modeling studies were used determine mechanism candidate focusing their interactions residues active site receptor-binding domain (RBD) SARS-CoV-2. This allowed us identify binding sites within RBD variants, demonstrating how is confidence future vivo testing safety effectiveness these warranted, given effective variant concerns.

Language: Английский

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