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

Viruses, Journal Year: 2024, Volume and Issue: 16(2), P. 168 - 168

Published: Jan. 23, 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 drug-effective concentration (IC50) increasing concentrations companion drug, although effect prominent minimal null These results support which should further investigated animal models before introduction into clinic.

Language: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 28, 2024

Synopsis Objectives Immunocompromised individuals are susceptible to severe COVID-19 and potentially contribute the emergence of variants with altered pathogenicity due persistent infection. This study investigated impact immunosuppression on SARS-CoV-2 infection in k18-hACE2 mice effectiveness antiviral treatments this context during first 7 days Methods Mice were immunosuppressed using cyclophosphamide infected a B lineage SARS-CoV-2. Molnupiravir nirmatrelvir, alone combination, administered viral load sequence diversity was assessed. Results Treatment but immune compromised 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 (Ts/Tv) ratio, representative A>G C>U mutations increase by co-administration molnupiravir. Notably, itself did appear promote mutational characteristic concern (VOCs). Conclusions Further investigations warranted fully understand role immunocompromised VOC development, especially taking persistence into consideration, inform optimised 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.

Language: Английский

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Further preclinical characterization of molnupiravir against SARS-CoV-2: Antiviral activity determinants and viral genome alteration patterns

Heliyon, Journal Year: 2024, Volume and Issue: 10(10), P. e30862 - e30862

Published: May 1, 2024

The SARS-CoV-2 pandemic has highlighted the need for broad-spectrum antiviral drugs to respond promptly viral emergence. We conducted a preclinical study of molnupiravir (MOV) against fully characterise its properties and mode action. activity different concentrations MOV was evaluated ex vivo on human airway epithelium (HAE) in hamster model at three escalating doses (150, 300 400 mg/kg/day) according regimens (preventive, pre-emptive curative). assessed loads infectious titres apical pole HAE lungs, trough concentration plasma lungs. To explore action MOV, entire genomes collected viruses were deep-sequenced. effectively reduced lungs treated animals. Early treatment after infection key factor efficacy, probably associated with high lung suggesting good accumulation lung. induced genomic alteration an increase number minority variants, predominant G A transitions. observed reduction replication mechanism leading lethal mutagenesis, supported by clinical trials showing humans, provide convincing basis further research as additional means fight COVID-19 other RNA viruses.

Language: Английский

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Combined Molnupiravir and Nirmatrelvir Treatment Improves the Inhibitory Effect on SARS-CoV-2 in Rhesus Macaques

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Sept. 5, 2022

Abstract The periodic emergence of SARS-CoV-2 variants concern (VOCs) with unpredictable clinical severity and ability to escape preexisting immunity emphasizes the continued need for antiviral interventions. Two small molecule inhibitors, molnupiravir (MK-4482), a nucleoside analog, nirmatrelvir (PF-07321332), 3C-like protease inhibitor, have each recently been approved as monotherapy use in high risk COVID-19 patients. As preclinical data are only available rodent ferret models, we originally assessed efficacy MK-4482 PF-07321332 alone then combination Against infection Delta VOC rhesus macaque model. Notably, improved individual inhibitory effect both drugs. Combined treatment resulted milder disease progression, stronger reduction virus shedding from mucosal tissues upper respiratory tract, viral replication lower reduced lung pathology. Our strongly indicate superiority combined infections demonstrated here closest surrogate One Sentence Summary inhibits more effectively than treatments

Language: Английский

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The hope and hype of ellagic acid and urolithins as ligands of SARS-CoV-2 Nsp5 and inhibitors of viral replication

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 38(1)

Published: Aug. 28, 2023

Non-structural protein 5 (Nsp5) is a cysteine protease that plays key role in SARS-CoV-2 replication, suppressing host synthesis and promoting immune evasion. The investigation of natural products as potential strategy for Nsp5 inhibition gaining attention means developing antiviral agents. In this work, we have investigated the physicochemical properties structure-activity relationships ellagic acid its gut metabolites, urolithins A-D, ligands Nsp5. Results allow us to identify urolithin D promising ligand Nsp5, with dissociation constant nanomolar range potency. Although able bind catalytic cleft appraisal viral replication against Vero E6 assay highlights lack activity. While these results are discussed framework available literature reporting conflicting data on polyphenol activity, they provide new clues inhibitors.

Language: Английский

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