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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Cyanobacteria and Algae-Derived Bioactive Metabolites as Antiviral Agents: Evidence, Mode of Action, and Scope for Further Expansion; A Comprehensive Review in Light of the SARS-CoV-2 Outbreak

Antioxidants, Journal Year: 2022, Volume and Issue: 11(2), P. 354 - 354

Published: Feb. 10, 2022

COVID-19-a severe acute respiratory syndrome disease caused by coronavirus 2 (SARS-CoV-2)-has recently attracted global attention, due to its devastating impact, the point of being declared a pandemic. The search for new natural therapeutic drugs is mandatory, as screening already-known antiviral so far has led poor results. Several species marine algae have been reported sources bioactive metabolites with potential and immunomodulatory activities, among others. Some these might be able act antimicrobial also against viral infections inhibiting their replication. Moreover, they could trigger immunity infection in humans used protective agents COVID-In this context, article reviews main activities from exploitation anti-SARS-CoV-2 drugs.

Language: Английский

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Therapeutic and diagnostic applications of nanoparticles in the management of COVID-19: a comprehensive overview

Virology Journal, Journal Year: 2022, Volume and Issue: 19(1)

Published: Dec. 3, 2022

In December 2019, Coronavirus Disease 2019 (COVID-19) was reported in Wuhan, China. Comprehensive strategies for quick identification, prevention, control, and remedy of COVID-19 have been implemented until today. Advances various nanoparticle-based technologies, including organic inorganic nanoparticles, created new perspectives this field. These materials were extensively used to control because their specific attribution preparing antiviral face masks, safety sensors, etc. review, the most current applications, achievements against coronavirus summarized highlighted. This paper also offers nanoparticle preventive, diagnostic, treatment options combat pandemic.

Language: Английский

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Roles of host proteases in the entry of SARS-CoV-2

Animal Diseases, Journal Year: 2023, Volume and Issue: 3(1)

Published: April 25, 2023

Abstract The spike protein (S) of SARS-CoV-2 is responsible for viral attachment and entry, thus a major factor host susceptibility, tissue tropism, virulence pathogenicity. S divided with S1 S2 region, the contains receptor-binding domain (RBD), while hydrophobic fusion entry into cell. Numerous proteases have been implicated in activation through various cleavage sites. In this article, we review including furin, trypsin, transmembrane protease serine 2 (TMPRSS2) cathepsins S. Many betacoronaviruses polybasic residues at S1/S2 site which subjected to by furin. facilitates more assessable RBD receptor ACE2, binding triggers further conformational changes exposure S2’ such as type II (TTPRs) TMPRSS2. presence TMPRSS2 on target cells, can utilize direct route envelope cellular membrane. absence TMPRSS2, enter cells via endosomes where multiple cleave successful entry. Additional involved were discussed. This article also includes roles 3C-like inhibitors inhibitory activity against cathepsin L SARS-CoV-2, discussed dual virus replication.

Language: Английский

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Discovery of novel papain-like protease inhibitors for potential treatment of COVID-19

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 254, P. 115380 - 115380

Published: April 17, 2023

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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Discovery of Pyrano[2,3-c]pyrazole Derivatives as Novel Potential Human Coronavirus Inhibitors: Design, Synthesis, In Silico, In Vitro, and ADME Studies

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(2), P. 198 - 198

Published: Feb. 2, 2024

The SARS-CoV-2 pandemic at the end of 2019 had major worldwide health and economic consequences. Until effective vaccination approaches were created, healthcare sectors endured a shortage operative treatments that might prevent infection’s spread. As result, academia pharmaceutical industry prioritized development SARS-CoV2 antiviral medication. Pyranopyrazoles have been shown to play prominent function in chemistry drug sighting because their significant bioactive properties. We provide herein novel sequence pyranopyrazoles annulated systems whose efficacy cytotoxicity explored versus human coronavirus 229E (HCoV-229E) Vero-E6 cell lines as model for Coronaviridae family. Fifteen synthetic congeners pointed out miscellaneous efficacies against HCoV-229E with variable inhibition degrees. Compound 18 showed high selectivity index (SI = 12.6) established spectacular inhibitory capacity 229E. Compounds 6, 7, 14 exposed moderate efficacies. 14, exhibited substantial action through replication phase reduction percentages extending from 53.6%, 60.7%, 55% 82.2%, correspondingly. Likewise, when assessed positive control tipranavir (88.6%), efficiency compounds Mpro provided 80.4%, 73.1%, 81.4% up 84.5%, respectively. In silico studies performed investigate further biological activity target compounds’ physical chemical features, including molecular dynamic (MD) simulations, protein–ligand docking, ADME studies, density functional theory (DFT) calculations. These inquiries demonstrated this series metabolically stable are inhibitors inhibit viral protein may emerged COVID-19 curative option.

Language: Английский

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The dual role of toll-like receptors in COVID-19: Balancing protective immunity and immunopathogenesis

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: unknown, P. 137836 - 137836

Published: Nov. 1, 2024

Language: Английский

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Toxicity assessment of SARS-CoV-2-derived peptides in combination with a mix of pollutants on zebrafish adults: A perspective study of behavioral, biometric, mutagenic, and biochemical toxicity

The Science of The Total Environment, Journal Year: 2022, Volume and Issue: 858, P. 159838 - 159838

Published: Nov. 4, 2022

Language: Английский

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Liposomal Lactoferrin Exerts Antiviral Activity against HCoV-229E and SARS-CoV-2 Pseudoviruses In Vitro

Viruses, Journal Year: 2023, Volume and Issue: 15(4), P. 972 - 972

Published: April 15, 2023

A limited number of effective therapies are currently available to treat human coronavirus SARS-CoV-2 and other coronaviruses, which responsible for nearly a third global cases the common cold. The possibility new emerging coronaviruses demands powerful antiviral strategies. Lactoferrin is well-known protein that possesses anti-inflammatory immunomodulatory activities, it has previously shown activity against several viruses, including SARS-CoV-2. To increase this activity, here we present bovine liposomal lactoferrin. Liposomal encapsulation compound was proven permeability, bioavailability, time release. In work, compare free lactoferrin HCoV229E in vitro primary bronchial epithelial cells, demonstrated form exerts more potent than its at non-cytotoxic doses.

Language: Английский

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