Stabilization of the Dimeric State of SARS-CoV-2 Main Protease by GC376 and Nirmatrelvir

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6062 - 6062

Published: March 23, 2023

The main protease (Mpro or 3CLpro) is an enzyme that evolutionarily conserved among different genera of coronaviruses. As it essential for processing and maturing viral polyproteins, Mpro has been identified as a promising target the development broad-spectrum drugs against Like SARS-CoV MERS-CoV, mature active form SARS-CoV-2 dimer composed identical subunits, each with single site. Individual monomers, however, have very low no catalytic activity. such, inhibition can be achieved by molecules substrate binding pocket to block activity dimerization process. In this study, we investigated GC376, transition-state analog inhibitor feline infectious peritonitis coronavirus, Nirmatrelvir (NMV), oral, bioavailable pan-human coronavirus antiviral Our results show both GC376 NMV are capable strongly altering monomer-dimer equilibrium stabilizing dimeric state. This behavior proposed related structured hydrogen-bond network established at site, where hydrogen bonds between Ser1' Glu166/Phe140 formed in addition those latter residues NMV.

Language: Английский

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The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19

Microbiology Spectrum, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

ABSTRACT Immunocompromised individuals are susceptible to severe coronavirus disease 2019 and potentially contribute the emergence of variants with altered pathogenicity due persistent infection. This study investigated impact immunosuppression on acute respiratory syndrome 2 (SARS-CoV-2) infection in K18-hACE2 mice effectiveness antiviral treatments this context during first 7 days Mice were immunosuppressed using cyclophosphamide infected a B lineage SARS-CoV-2. Molnupiravir nirmatrelvir, alone combination, administered, viral load sequence diversity assessed. Treatment but immunocompromised both compounds either singly or combination resulted decreased loads pathological changes compared untreated animals. also abrogated neuronal tissue. However, no consistent consensus observed, except for S:H655Y mutation. Molnupiravir, not nirmatrelvir alone, increased transition/transversion ratio, representative G > A C U mutations, increase was by co-administration molnupiravir. Notably, itself did appear promote mutational characteristics concern (VOCs). Further investigations warranted fully understand role VOC development, especially taking persistence into consideration, inform optimized public health strategies. It is more likely that immunodeficiency promotes does necessarily lead substantial consensus-level absence selection pressure. Consistent mechanisms action, molnupiravir showed stronger mutagenic effect than model. IMPORTANCE The central aim risk-assess administering compound, molnupiravir, patients believed already be at risk generating diversity, which could have implications resistance development. Combination therapy has long history mitigating used demonstrate its potential usefulness context. Animals treated an ratios over time, drug’s mechanism action recent UK-wide phase II clinical trial assessing efficacy humans. addition clearance, turn reduces probability rapid intra-host evolution

Language: Английский

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Effectiveness of early intervention and combination treatment with monoclonal antibodies and antivirals in oncohematological patients with SARS-CoV-2: a retrospective experience

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 28, 2025

Patients with acute SARS-CoV-2 and pre-existing oncohematological conditions challenge clinicians due to a heightened risk for severe COVID-19 forced deferral of cancer treatment. Different treatment approaches aim either prevent the progression mild disease ("early therapy") or treat more COVID-19. Currently, there is limited evidence supporting effectiveness tailored approach patients. We present real-world experience from two university hospitals. In this retrospective study we recruited patients hospitalized pneumonia between March 2020 June 2023 hospitals in Latium, Italy. received antiviral monoclonal antibodies (MoAb) alone, dual therapy (antiviral MoAb) triple (two different antivirals MoAb). The aimed evaluate practical management focused on impact related specific therapies, early treatment, tixagevimab-cilgavimab prophylaxis in-hospital mortality viral clearance time. Overall, 101 were recruited, 76 (75.24%) developed pneumonia, 16 (15.84%) died any cause. While most (75,25%) did not receive "early therapy", those who had higher chance survival (p=0.04). Furthermore, subgroup treated demonstrated rate as well (p=0.02). Out resulted lower (all survive group). This group also showed significant reduction time first day evaluated (6 days [IQR 4;9]), compared only remdesivir (17 8;37]) (p=0.03). Our findings demonstrate that significantly reduces mortality, while accelerates These results, line recent studies, underscore critical importance prompt multitargeted pharmacological optimizing outcomes SARS-CoV-2. Future research, involving larger cohorts, should delve deeper into strategies vulnerable population, particular emphasis elderly, continue high rates.

Language: Английский

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Antiviral therapies for the management of persistent coronavirus disease 2019 in immunocompromised hosts: A narrative review

Transplant Infectious Disease, Journal Year: 2024, Volume and Issue: 26(3)

Published: May 29, 2024

Abstract Antiviral agents with activity against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) have played a critical role in disease management; however, little is known regarding the efficacy of these medications treatment SARS‐CoV‐2 infection immunocompromised patients, particularly management persistent positivity. This narrative review discusses 2019 hosts, focus on antiviral therapies. We identified 84 cases from literature describing variety approaches, including prolonged therapy ( n = 11), combination antivirals 13), and mixed antibody treatments 60). A high proportion had an underlying haematologic malignancy 67, 80%), were receipt anti‐CD20 51, 60%). Success was reported 70 (83%) which varied according to type. Combination therapies may be effective approach for individuals positivity, those that incorporate aimed at increasing neutralizing levels. Any novel approaches taken this difficult dilemma should mindful emergence resistance.

Language: Английский

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An Overview on Anti-COVID-19 Drug Achievements and Challenges Ahead

ACS Pharmacology & Translational Science, Journal Year: 2023, Volume and Issue: 6(9), P. 1248 - 1265

Published: Aug. 16, 2023

The appearance of several coronavirus pandemics/epidemics during the last two decades (SARS-CoV-1 in 2002, MERS-CoV 2012, and SARS-CoV-2 2019) indicates that humanity will face increasing challenges from coronaviruses future. emergence new strains with similar transmission characteristics as mortality rates to SARS-CoV-1 (∼10% mortality) or (∼35% future is a terrifying possibility. Therefore, getting enough preparations such risks an inevitable necessity. present study aims review drug achievements fight against combined perspective derived pharmacology, pharmacotherapy, medicinal chemistry insights. Appreciating all efforts made past few years, there strong evidence desired results have not yet been achieved research this area should still be pursued seriously. By expressing some pessimistic possibilities concluding discovery pharmacotherapy COVID-19 successful so far, short essay tries draw attention responsible authorities more prepared epidemics/pandemics.

Language: Английский

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Recent updates on the biological efficacy of approved drugs and potent synthetic compounds against SARS-CoV-2

RSC Advances, Journal Year: 2023, Volume and Issue: 13(6), P. 3677 - 3687

Published: Jan. 1, 2023

The role of functional group in discovery Nirmatrelvir is valuable and interesting for development various inhibitors against viral diseases.

Language: Английский

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Efficacy of Remdesivir and Neutralizing Monoclonal Antibodies in Monotherapy or Combination Therapy in Reducing the Risk of Disease Progression in Elderly or Immunocompromised Hosts Hospitalized for COVID-19: A Single Center Retrospective Study

Viruses, Journal Year: 2023, Volume and Issue: 15(5), P. 1199 - 1199

Published: May 19, 2023

Introduction: Remdesivir (REM) and monoclonal antibodies (mAbs) could alleviate severe COVID-19 in at-risk outpatients. However, data on their use hospitalized patients, particularly elderly or immunocompromised hosts, are lacking. Methods: All consecutive patients with at our unit from 1 July 2021 to 15 March 2022 were retrospectively enrolled. The primary outcome was the progression (P/F < 200). Descriptive statistics, a Cox univariate–multivariate model, an inverse probability treatment-weighted (IPTW) analysis performed. Results: Overall, 331 subjects included; median (q1–q3) age 71 (51–80) years, they males 52% of cases. Of them, 78 (23%) developed COVID-19. All-cause in-hospital mortality 14%; it higher those disease (36% vs. 7%, p 0.001). REM mAbs resulted 7% (95%CI = 3–11%) 14% 3–25%) reduction risk COVID-19, respectively, after adjusting IPTW. In addition, by evaluating only combination associated significantly lower incidence (aHR 0.06, 95%CI 0.02–0.77) when compared monotherapy. Conclusions: may reduce patients. Importantly, be beneficial.

Language: Английский

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Tixagevimab/Cilgavimab: Still a Valid Prophylaxis against COVID-19 New Variants?

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 354 - 354

Published: Feb. 25, 2024

Background: this study aims to evaluate the efficacy of tixagevimab/cilgavimab (Evusheld™) against various SARS-CoV-2 variants, including newer Omicron sublineages, in an immunocompromised cohort and vitro. Study design: Conducted Italy, research involves patients who received Evusheld. It evaluates serum neutralization activity different strains (20A.EU1, BA.5, BQ.1, XBB.1.5, XBB.1.16, EG.5) before (T0), after 14 (T1), 30 (T2) days from injection. Furthermore, vitro Evusheld VOCs was evaluated. Results: The composed 72 patients. neutralizing tixagevimab/cilgavimab-treated notably lower variants such as EG.5. Then, detailed specific EC50 values quantify VOCs. Newer like BQ.1 XBB.1.5 exhibited neutralization, underscoring challenges effectively countering evolving virus. Interestingly, maintained reduced but still valid EG.5 with 189 ng/mL Cmax/EC90 110.7. Conclusions: Tixagevimab/cilgavimab wanes novel subvariants. This underscores critical need for ongoing adaptation vigilance prophylactic strategies counter dynamic unpredictable nature COVID-19 pandemic.

Language: Английский

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Functional assessments of SARS-CoV-2 single-round infectious particles with variant-specific spike proteins on infectivity, drug sensitivity, and antibody neutralization

Antiviral Research, Journal Year: 2023, Volume and Issue: 220, P. 105744 - 105744

Published: Nov. 7, 2023

Language: Английский

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In Vitro Combinatorial Activity of Direct Acting Antivirals and Monoclonal Antibodies against the Ancestral B.1 and BQ.1.1 SARS-CoV-2 Viral Variants

Published: Jan. 3, 2024

Combination antiviral therapy may be helpful in the treatment of SARS-CoV-2 infection, however no clinical trial data are available and combined use direct acting antivirals (DAA) monoclonal antibodies (mAb) has been reported only anecdotally. To assess cooperative effects dual drug combinations vitro, we used a VERO E6 cell based vitro system with ancestral B.1 or highly divergent BQ.1.1 virus to test pairwise licensed DAA, including nirmatrelvir (NRM), remdesivir (RDV) active metabolite molnupiravir (EIDD-1931) as well combination RDV four mAbs (sotrovimab, bebtelovimab, cilgavimab, tixagevimab; tested susceptible virus). According SynergyFinder 3.0 summary weighted scores, all had an additive effect. Within DAA/DAA combinations, paired scores variants were comparable. In post-hoc analysis weighting synergy by concentrations, several cases synergistic detected at specific both for RDV/mAb combinations. This was supported confirmation experiments showing more than linear shift effective concentration (IC50) increasing concentrations companion drug, although effect prominent but minimal null These results support which should further investigated animal models before introduction into clinic.

Language: Английский

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