The hope and hype of ellagic acid and urolithins as ligands of SARS-CoV-2 Nsp5 and inhibitors of viral replication DOI Creative Commons
Elisa Bianconi, Anna Gidari, Maria Souma

et al.

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

Triple Combination Therapy With 2 Antivirals and Monoclonal Antibodies for Persistent or Relapsed Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Immunocompromised Patients DOI Open Access
Małgorzata Mikulska, Chiara Sepulcri, Chiara Dentone

et al.

Clinical Infectious Diseases, Journal Year: 2023, Volume and Issue: 77(2), P. 280 - 286

Published: March 28, 2023

Severely immunocompromised patients are at risk for prolonged or relapsed Coronavirus Disease 2019 (COVID-19), leading to increased morbidity and mortality. We aimed evaluate efficacy safety of combination treatment in COVID-19 patients.We included all with prolonged/relapsed treated therapy 2 antivirals (remdesivir plus nirmatrelvir/ritonavir, molnupiravir case renal failure) plus, if available, anti-spike monoclonal antibodies (mAbs), between February October 2022. The main outcomes were virological response day 14 (negative Severe Acute Respiratory Syndrome [SARS-CoV-2] swab) clinical (alive, asymptomatic, negative SARS-CoV-2 30 the last follow-up.Overall, 22 (Omicron variant 17/18) included: 18 received full mAbs 4 only; 20 (91%) patients, nirmatrelvir/ritonavir remdesivir. Nineteen (86%) had hematological malignancy, 15 (68%) anti-CD20 therapy. All symptomatic; 8 (36%) required oxygen. Four a second course treatment. rate 14, 30, follow-up was 75% (15/20 evaluable), 73% (16/22), 82% (18/22), respectively. Day rates significantly higher when mAbs. Higher number vaccine doses associated better final outcome. Two (9%) developed severe side effects (bradycardia remdesivir discontinuation myocardial infarction).Combination including (mainly nirmatrelvir/ritonavir) high COVID-19.

Language: Английский

Citations

99
SARS-CoV-2 Drug Resistance and Therapeutic Approaches DOI Creative Commons

Sania Batool,

Santosh Chokkakula, Ju Hwan Jeong

et al.

Heliyon, Journal Year: 2025, Volume and Issue: 11(2), P. e41980 - e41980

Published: Jan. 1, 2025

Language: Английский

Citations

3
Nirmatrelvir and COVID-19: development, pharmacokinetics, clinical efficacy, resistance, relapse, and pharmacoeconomics DOI
Daniele Focosi, Scott A. McConnell, Shmuel Shoham

et al.

International Journal of Antimicrobial Agents, Journal Year: 2023, Volume and Issue: 61(2), P. 106708 - 106708

Published: Jan. 2, 2023

Language: Английский

Citations

32
Combination regimen of nirmatrelvir/ritonavir and molnupiravir for the treatment of persistent SARS-CoV-2 infection: A case report and a scoping review of the literature DOI Creative Commons
Davide Marangoni, Roberta Maria Antonello, Marco Coppi

et al.

International Journal of Infectious Diseases, Journal Year: 2023, Volume and Issue: 133, P. 53 - 56

Published: May 5, 2023

Immunocompromised patients still experience unpredictable courses of COVID-19, despite that effective vaccines and drugs against SARS-CoV-2 are now available. Antiviral combination regimens may have a role in infection immunocompromised hosts, but current knowledge is limited. We describe the case 73-year-old Italian man affected by follicular lymphoma with persistent who was successfully treated co-administration oral antivirals (10-day molnupiravir nirmatrelvir/ritonavir). The therapy well tolerated both from clinical biochemical standpoint, no signs toxicity. also performed scoping review, to sum up available on combined antiviral including remdesivir, molnupiravir, or nirmatrelvir/ritonavir. Pending further studies larger cohorts patients, our report consistent pre-clinical data, supporting possible use selected difficult-to-treat COVID-19 cases.

Language: Английский

Citations

27
Early combination therapy of COVID-19 in high-risk patients DOI Creative Commons
Hans Martin Orth,

Charlotte Flasshove,

Moritz Berger

et al.

Infection, Journal Year: 2023, Volume and Issue: 52(3), P. 877 - 889

Published: Nov. 29, 2023

Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this certainty. Dual therapies may therefore have a synergistic effect.

Language: Английский

Citations

24
Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2 DOI Creative Commons

Jessica Wagoner,

Shawn Herring,

Tien-Ying Hsiang

et al.

Microbiology Spectrum, Journal Year: 2022, Volume and Issue: 10(5)

Published: Oct. 3, 2022

Imagine a future viral pandemic where if you test positive for the new virus, can quickly take some medicines at home few days so that do not get too sick. To date, only single drugs have been approved outpatient use against SARS-CoV-2, and we are learning these limitations may succumb to drug resistance.

Language: Английский

Citations

36
Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques DOI Creative Commons
Kyle Rosenke,

Matt C. Lewis,

Friederike Feldmann

et al.

JCI Insight, Journal Year: 2022, Volume and Issue: 8(4)

Published: Dec. 27, 2022

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 recently been approved as monotherapy use in high-risk patients COVID-19. As preclinical data are only available rodent ferret models, here we assessed efficacy MK-4482 PF-07321332 alone combination against infection Delta VOC rhesus macaque COVID-19 model. Macaques were infected variant treated vehicle, MK-4482, PF-07321332, or PF-07321332. Clinical exams performed at 1, 2, 4 days postinfection assess disease virological parameters. Notably, improved individual inhibitory effect both drugs, resulting milder progression, stronger reduction virus shedding from mucosal tissues upper respiratory tract, viral replication lower reduced lung pathology. Our strongly indicate superiority combined treatment infections demonstrated closest surrogate model human infection.

Language: Английский

Citations

31
A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients DOI Creative Commons
Claudia Alteri, Valeria Fox, Rossana Scutari

et al.

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Dec. 15, 2022

Abstract Little is known about SARS-CoV-2 evolution under Molnupiravir and Paxlovid, the only antivirals approved for COVID-19 treatment. By investigating variability in 8 Molnupiravir-treated, 7 Paxlovid-treated 5 drug-naïve individuals at 4 time-points (Days 0-2-5-7), a higher genetic distance found pressure compared to Paxlovid no-drug (nucleotide-substitutions/site mean±Standard error: 18.7 × 10 −4 ± 2.1 vs. 3.3 0.8 3.1 , P = 0.0003), peaking between Day 2 5. drives emergence of more G-A C-T transitions than other mutations ( 0.031). selective does not differ from that or pressure, except orf8 (dN > dS, 0.001); few amino acid are enriched specific sites. No RNA-dependent RNA polymerase (RdRp) main proteases (Mpro) conferring resistance found. This proof-of-concept study defines within-host during antiviral treatment, confirming vivo induced by drug-naive, albeit resulting apparent mutation selection.

Language: Английский

Citations

23
Synergistic Activity of Remdesivir–Nirmatrelvir Combination on a SARS-CoV-2 In Vitro Model and a Case Report DOI Creative Commons
Anna Gidari, Samuele Sabbatini, Elisabetta Schiaroli

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(7), P. 1577 - 1577

Published: July 19, 2023

Background: This study aims to investigate the activity of remdesivir–nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and report a case Coronavirus Disease 2019 (COVID-19) cured with this combination. Methods: A Vero E6 cell-based infection assay was used in vitro The SARS-CoV-2 strains tested were 20A.EU1, BA.1 BA.5. After incubation, viability performed. supernatants collected for viral titration. Highest Single Agent (HSA) reference model calculated. An HSA score >10 is considered synergic. Results: Remdesivir nirmatrelvir showed synergistic at 48 72 h, an 52.8 28.6, respectively (p < 0.0001). These data confirmed by performing supernatant titration omicron variants: reduced titer better than more active compound alone. immunocompromised patient prolonged critical COVID-19 successfully treated remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab dexamethasone, excellent clinical–radiological response. However, she required further off-label therapy nirmatrelvir/ritonavir until negative. Conclusions: Remdesivir–nirmatrelvir has synergic vitro. may have role immunosuppressed patients severe shedding.

Language: Английский

Citations

15
Viral target and metabolism‐based rationale for combined use of recently authorized small molecule COVID‐19 medicines: Molnupiravir, nirmatrelvir, and remdesivir DOI Creative Commons

Daisy Yan,

Bingfang Yan

Fundamental and Clinical Pharmacology, Journal Year: 2023, Volume and Issue: 37(4), P. 726 - 738

Published: March 18, 2023

Abstract The COVID‐19 pandemic remains a major health concern worldwide, and SARS‐CoV‐2 is continuously evolving. There an urgent need to identify new antiviral drugs develop novel therapeutic strategies. Combined use of newly authorized medicines including molnupiravir, nirmatrelvir, remdesivir has been actively pursued. Mechanistically, nirmatrelvir inhibits replication by targeting the viral main protease (M pro ), critical enzyme in processing immediately translated coronavirus polyproteins for replication. Molnupiravir remdesivir, on other hand, inhibit RNA‐dependent RNA‐polymerase (RdRp), which directly responsible genome production subgenomic RNAs. targets RdRp induces severe RNA mutations (genome), commonly referred as error catastrophe. Remdesivir, contrast, causes chain termination arrests synthesis genome. In addition, all three undergo extensive metabolism with strong significance. hydrolytically activated carboxylesterase‐2 (CES2), inactivated cy tochrome P 450‐based oxidation (e.g., CYP3A4), CES1 but covalently CES2. Additionally, are oxidized same CYP enzymes. distinct mechanisms action provide rationale their combined use. On these that determines potential. This review discusses how pathways enzymes involved should be carefully considered during synergy.

Language: Английский

Citations

11