In the age of Omicron variant: Paxlovid raises new hopes of COVID‐19 recovery

Journal of Medical Virology, Journal Year: 2021, Volume and Issue: 94(5), P. 1766 - 1767

Published: Dec. 22, 2021

Since the outbreak of COVID-19, caused by SARS-CoV-2, in December 2019, ongoing pandemic has posed 5 318 216 deaths worldwide.1 Vaccines, traditional Chinese medicine, and small-molecule antiviral therapies were considered emergency responders on COVID-19.2 However, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) variants SARS-CoV-2 cause resurge infections. More worrisome, novel Omicron (B.1.1.529) variant, firstly identified South Africa November 24, 2021, put whole world red alert.3 Based unprecedented number mutations (>32 Spike), enhanced transmissibility (three times more infectious or severe than original Wuhan strain), 26, World Health Organization announced it to be a variant concern.4 Therefore, some necessary measures, such as wearing masks, getting vaccine booster doses, restricting gatherings, travel restrictions, increasing vaccination coverage (e.g., >80% people have not had single dose5), gene sequencing could help reduce spread globally. As stands, early data hint that might alter responses COVID-19 vaccines weaken protection, almost all targeted at S protein.6 for small molecule drugs, only an intravenous nucleotide prodrug remdesivir (Veklury®) was currently approved U.S. FDA treatment infection, but is difficult widely used hospitalized patients due its limitations controversial efficacy.7 Only very recently, oral candidate Paxlovid™ (PF-07321332 + ritonavir), developed Pfizer Inc., raises new hopes recovery age variant.8 PF-07321332, second-generation orally bioavailable main protease (Mpro) inhibitor molecular entity combines merits both PF-07304814 boceprevir.9-13 recognized promising broad-spectrum agent, can treat infections with multiple human coronaviruses vitro, including SARS-CoV, HCoV-HKU1, HCoV-OC43, MERS-CoV, HCoV-229E, HCoV-NL63.8 Owen et al. revealed PF-07321332 exhibits strong anti-SARS-CoV-2 Mpro activity Vero E6 cells half maximal effective concentration value 74.5 nM without significant cytotoxicity.8 In addition, enhance mouse-adapted MA10 model, resulting significantly reduced multifocal pulmonary lesions viral load mouse lungs dose-dependent manner.8 found safe well-tolerated no adverse dosing 600 mg/kg/day monkeys 1000 rats 14 days.8 favorable bioavailability pharmacokinetic properties preclinical absorption, distribution, metabolism, excretion studies, supporting progression into clinical studies. To elucidate inhibitory mechanism level, Rao determined 1.6-Å crystal structure complex (PDB: 7VH8), which indicates binds enzyme via covalent linkage Cys145 nitrile carbon form reversible thioimidate adduct.14 Specifically, Nitsche's vitro suggest mutants remain susceptible PF-07321332.15 They expressed five prevalent (including G15S, T21I, L89F, K90R, L205V) different lineages, kinetics showed potency against above-mentioned variants, implying management SARS-CoV-2.15 P132H mutant detected nsp5 (Mpro), structural analysis demonstrated this kept away from active site may hinder performance agents.16 Neyts (250 mg/kg, twice daily) completely protect Syrian golden hamsters intranasal infection variants.17 achieve trials, combined ritonavir, HIV drug slow down metabolism through inhibiting cytochrome P450 enzymes.18 For example, double-blind, placebo-controlled phase II/III trial conducted Inc. evaluate efficacy 1219 nonhospitalized high-risk adult COVID-19.19 The interim results 89% reduction risk COVID-19-related hospitalization death any compared placebo administered within three days symptom onset.19 Notably, does appear preventing high statistical significance (0/607 group vs. 10/612 group, p < 0.0001).19 This finding supports potential therapy patients. Moreover, trials (Clinical Trials Registration NCT04962022, NCT04962230, NCT04756531) been completed, (NCT04960202, NCT05064800, NCT05005312, NCT05032950, NCT05047601) are underway will disclosed shortly. It noted, however, widespread use misuse increase required resistance. Anyway, we sincerely hope Pfizer's prove variant. study supported project PhD research start-up fund Qufu Normal University, China (Grant nos: 614901 615201). authors declare there conflict interests. Zhonglei Wang: Conceptualization, writing—original draft, writing—review editing, visualization, funding acquisition. Liyan Yang:

Language: Английский

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Bioactive natural products in COVID-19 therapy

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 19, 2022

The devastating COVID-19 pandemic has caused more than six million deaths worldwide during the last 2 years. Effective therapeutic agents are greatly needed, yet promising magic bullets still do not exist. Numerous natural products (cordycepin, gallinamide A, plitidepsin, telocinobufagin, and tylophorine) have been widely studied play a potential function in treating COVID-19. In this paper, we reviewed published studies (from May 2021 to April 2022) relating closely bioactive (isolated from medicinal plants, animals products, marine organisms) therapy

Language: Английский

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Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Dec. 6, 2022

GS-441524, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is a 1′-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS‐441524 poses challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, intravenously administered version (version 1.0) first FDA-approved agent for SARS-CoV-2 treatment. clinical trials have presented conflicting evidence on value remdesivir in COVID-19. Therefore, GS-441524 derivatives (VV116, ATV006, and GS-621763; 2.0, targeting highly conserved viral RdRp) could be considered as game-changers treating COVID-19 because administration has potential maximize benefits, including decreased duration reduced post-acute sequelae infection, well limited side effects such hepatic accumulation. This review summarizes current research related provides important insights into factors underlying controversial observations regarding efficacy remdesivir; overall, it offers effective launching pad developing GS-441524.

Language: Английский

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Comparative evaluation of authorized drugs for treating Covid‐19 patients

Health Science Reports, Journal Year: 2022, Volume and Issue: 5(4)

Published: June 13, 2022

Abstract Background and Aims Vaccines are the first line of defense against coronavirus disease 2019 (Covid‐19). However, antiviral drugs provide a new tool to fight Covid‐19 pandemic. Here we aimed for comparative evaluation authorized treating patients. Methods We searched in PubMed Google Scholar using keywords terms such as Covid, SARS‐CoV‐2, Coronavirus 2019, therapeutic management, hospitalized patients, treatment. also gathered information from reputed newspapers, web portals, websites. thoroughly observed, screened, included studies relevant our inclusion criteria. only United States Food Drug Administration (FDA) this review. Results found that molnupiravir paxlovid available oral use, remdesivir is Paxlovid combination nirmatrelvir ritonavir, protease inhibitor (ritonavir increases concentration nirmatrelvir), other two (remdesivir molnupiravir) nucleoside analog prodrugs. Remdesivir doses do not need adjust renal hepatic impairment. dose adjustment required mild moderate or impaired Also, drug allowed patients with severe Preliminary showed significantly reduce hospitalization death among Moreover, US FDA has approved four monoclonal antibodies Studies suggest these would risk severity symptoms. World Health Organization strongly recommended use corticosteroids along critically Conclusion All effective inhibiting viral replication most SARS‐CoV‐2 variants. Therefore, vaccines, might potentially aid fighting

Language: Английский

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Serial viral load analysis by DDPCR to evaluate FNC efficacy and safety in the treatment of mild cases of COVID-19

Frontiers in Medicine, Journal Year: 2023, Volume and Issue: 10

Published: March 14, 2023

Introduction The SARS-CoV-2 outbreak has threatened the human population globally as numbers of reinfection cases even after large-scale vaccination. Trials have been carried out to find drugs effective in fighting disease, COVID-19 is being considered a treatable disease only we antivirals. A clinical candidate originally developed for HIV treatment, AZVUDINE (FNC), promising drug treatment COVID-19. Methods To predict outcome COVID-19, examined course viral load, every 48 h, by RT-PCR, and severity using an antiviral drug, FNC, with 281 participants. randomized trial was performed evaluate efficacy FNC added standard compared placebo group patients mild RT-qPCR ddPCR were applied estimate load samples from patients. Also, improvement evaluated well liver kidney function. Results discussion Notably, may shorten time nucleic acid negative conversion (NANC) versus group. In addition, reducing these present results showed that accelerate elimination virus could reduce save lot medical resources, making it strong outpatient home Clinical registration https://clinicaltrials.gov/ct2/show/NCT05033145 , identifier NCT05033145.

Language: Английский

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Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants

Metabolites, Journal Year: 2023, Volume and Issue: 13(2), P. 309 - 309

Published: Feb. 20, 2023

The nucleoside analog β-D-N4-hydroxycytidine is the active metabolite of prodrug molnupiravir and accepted as an efficient drug against COVID-19. Molnupiravir targets RNA-dependent RNA polymerase (RdRp) enzyme, which responsible for replicating viral genome during replication process certain types viruses. It works by disrupting normal function RdRp causing it to make mistakes genome. These can prevent from being transcribed, converted into a complementary DNA template, translated, or functional protein. By these crucial steps in process, effectively inhibit virus reduce its ability cause disease. This review article sheds light on impact SARS-CoV-2 variants concern, such delta, omicron, hybrid/recombinant variants. detailed mechanism molecular interactions using docking dynamics have also been covered. safety tolerability patients with comorbidities emphasized.

Language: Английский

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The Therapeutic Potential of Natural Dietary Flavonoids against SARS-CoV-2 Infection

Nutrients, Journal Year: 2023, Volume and Issue: 15(15), P. 3443 - 3443

Published: Aug. 3, 2023

The exploration of non-toxic and cost-effective dietary components, such as epigallocatechin 3-gallate myricetin, for health improvement disease treatment has recently attracted substantial research attention. recent COVID-19 pandemic provided a unique opportunity the investigation identification components capable treating viral infections, well gathering evidence needed to address major challenges presented by public emergencies. Dietary hold great potential starting point further drug development prevention SARS-CoV-2 infection owing their good safety, broad-spectrum antiviral activities, multi-organ protective capacity. Here, we review current knowledge characteristics-chemical composition, bioactive properties, putative mechanisms action-of natural flavonoids with targeting its variants. Notably, present promising strategies (combination therapy, lead optimization, delivery) overcome inherent deficiencies flavonoids, limited bioavailability poor stability.

Language: Английский

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After the Hurricane: Anti-COVID-19 Drugs Development, Molecular Mechanisms of Action and Future Perspectives

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 739 - 739

Published: Jan. 6, 2024

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a new coronavirus in the

Language: Английский

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Post-acute Sequelae of SARS-CoV-2 Infection: A Neglected Public Health Issue

Frontiers in Public Health, Journal Year: 2022, Volume and Issue: 10

Published: June 17, 2022

OPINION article Front. Public Health, 17 June 2022Sec. Health Education and Promotion https://doi.org/10.3389/fpubh.2022.908757

Language: Английский

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Plants as Biofactories for Therapeutic Proteins and Antiviral Compounds to Combat COVID-19

Life, Journal Year: 2023, Volume and Issue: 13(3), P. 617 - 617

Published: Feb. 23, 2023

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) had a profound impact on the world’s health and economy. Although end pandemic may come in 2023, it is generally believed that virus will not be completely eradicated. Most likely, become an endemicity. rapid development vaccines different types (mRNA, subunit protein, inactivated virus, etc.) some other antiviral drugs (Remdesivir, Olumiant, Paxlovid, has provided effectiveness reducing COVID-19’s worldwide. However, circulating SARS-CoV-2 been constantly mutating with emergence multiple variants, which makes control COVID-19 difficult. There still pressing need for developing more effective to fight against disease. Plants have promising production platform both bioactive chemical compounds (small molecules) recombinant therapeutics (big molecules). naturally produce diverse range as secondary metabolites, such alkaloids, terpenoids/terpenes polyphenols, are rich source countless compounds. can also genetically engineered valuable therapeutics. This molecular farming plants unprecedented opportunity vaccines, antibodies, biologics diseases because its potential advantages, low cost, safety, high volume. review summarizes latest advancements plant-derived used combat discusses prospects challenges plant-based agents.

Language: Английский

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