Combinatorial Regimens Augment Drug Monotherapy for SARS-CoV-2 Clearance in Mice DOI Open Access
Irfan Ullah, Fanny Escudié, Ivan Scandale

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 1, 2023

Summary Direct acting antivirals (DAAs) represent critical tools for combating SARS-CoV-2 variants of concern (VOCs) that evolve to escape spike-based immunity and future coronaviruses with pandemic potential. Here, we used bioluminescence imaging evaluate therapeutic efficacy DAAs target RNA-dependent RNA polymerase (favipiravir, molnupiravir) or Main protease (nirmatrelvir) against Delta Omicron VOCs in K18-hACE2 mice. Nirmatrelvir displayed the best followed by molnupiravir favipiravir suppressing viral loads lung. Unlike neutralizing antibody treatment, DAA monotherapy did not eliminate However, targeting two enzymes combining nirmatrelvir resulted superior virus clearance. Furthermore, Caspase-1/4 inhibitor mitigated inflammation lung pathology whereas COVID-19 convalescent plasma yielded rapid clearance 100% survival. Thus, our study provides insights into treatment efficacies other effective combinations bolster arsenal.

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
Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants DOI Creative Commons
Divya Teli, Pankti C. Balar, Kishan Patel

et al.

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

Citations

29
B-cell-depleted patients with persistent SARS-CoV-2 infection: combination therapy or monotherapy? A real-world experience DOI Creative Commons
Alessandra D’Abramo, Serena Vita, Alessia Beccacece

et al.

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Feb. 29, 2024

Objectives The aim of the study was to describe a cohort B-cell-depleted immunocompromised (IC) patients with prolonged or relapsing COVID-19 treated monotherapy combination therapy. Methods This is multicenter observational retrospective conducted on IC consecutively hospitalized SARS-CoV-2 infection from November 2020 January 2023. subjects were stratified according anti-SARS-CoV-2 therapy received. Results Eighty-eight enrolled, 19 under and 69 population had history immunosuppression (median 2 B-cells/mm 3 , IQR 1–24 cells), residual hypogammaglobulinemia observed in 55 patients. A reduced length hospitalization time negative molecular nasopharyngeal swab (NPS) versus group observed. In univariable multivariable analyses, percentage change rate days NPS negativity showed significant reduction receiving compared those monotherapy. Conclusion persistent patients, it essential explore new therapeutic strategies such as multi-target (antiviral double antiviral plus antibody-based therapies) avoid viral shedding and/or severe infection.

Language: Английский

Citations

13
Bioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens DOI Creative Commons
Irfan Ullah, Fanny Escudié, Ivan Scandale

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109049 - 109049

Published: Jan. 30, 2024

Language: Английский

Citations

6
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
Combination Therapy with UV-4B and Molnupiravir Enhances SARS-CoV-2 Suppression DOI Creative Commons

Evelyn J. Franco,

George L. Drusano,

Kaley C. Hanrahan

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(5), P. 1175 - 1175

Published: May 16, 2023

The host targeting antiviral, UV-4B, and the RNA polymerase inhibitor, molnupiravir, are two orally available, broad-spectrum antivirals that have demonstrated potent activity against SARS-CoV-2 as monotherapy. In this work, we evaluated effectiveness of UV-4B EIDD-1931 (molnupiravir's main circulating metabolite) combination regimens beta, delta, omicron BA.2 variants in a human lung cell line. Infected ACE2 transfected A549 (ACE2-A549) cells were treated with both monotherapy combination. Viral supernatant was sampled on day three when viral titers peaked no-treatment control arm, levels infectious virus measured by plaque assay. drug-drug effect interaction between also defined using Greco Universal Response Surface Approach (URSA) model. Antiviral evaluations treatment plus enhanced antiviral all relative to These results accordance those obtained from model, these identified additive beta synergistic delta variant. Our findings highlight anti-SARS-CoV-2 potential regimens, present therapy promising therapeutic strategy SARS-CoV-2.

Language: Английский

Citations

7
Triple antiviral treatment for COVID-19 in an immunocompromised patient DOI
Chiara Dentone, Małgorzata Mikulska, Chiara Sepulcri

et al.

Journal of Antimicrobial Chemotherapy, Journal Year: 2023, Volume and Issue: 78(8), P. 2097 - 2099

Published: May 25, 2023

Journal Article Triple antiviral treatment for COVID-19 in an immunocompromised patient Get access Chiara Dentone, Dentone Division of Infectious Diseases, IRCCS Ospedale Policlinico San Martino, Genoa, Italy https://orcid.org/0000-0002-9096-5812 Search other works by this author on: Oxford Academic PubMed Google Scholar Malgorzata Mikulska, Mikulska ItalyDivision Department Health Sciences (DISSAL), University Via Pastore, 1, 16132 Sepulcri, Sepulcri Corresponding author. E-mail: [email protected] https://orcid.org/0000-0003-1761-436X Elisa Balletto, Balletto Vanessa De Pace, Pace Hygiene Unit, Sabrina Beltramini, Beltramini Pharmacology Matteo Bassetti Antimicrobial Chemotherapy, dkad159, https://doi.org/10.1093/jac/dkad159 Published: 25 May 2023

Language: Английский

Citations

6
Mercapto-pyrimidines are reversible covalent inhibitors of the papain-like protease (PLpro) and inhibit SARS-CoV-2 (SCoV-2) replication DOI Creative Commons
Teena Bajaj, Eddie Wehri,

Rahul K. Suryawanshi

et al.

RSC Advances, Journal Year: 2023, Volume and Issue: 13(26), P. 17667 - 17677

Published: Jan. 1, 2023

The papain-like protease (PLpro) plays a critical role in SARS-CoV-2 (SCoV-2) pathogenesis and is essential for viral replication allowing the virus to evade host immune response. Inhibitors of PLpro have great therapeutic potential, however, developing them has been challenging due PLpro's restricted substrate binding pocket. In this report, we screened 115 000-compound library inhibitors identified new pharmacophore, based on mercapto-pyrimidine fragment that reversible covalent inhibitor (RCI) inhibits cells. Compound 5 had an IC50 5.1 μM inhibition hit optimization yielded derivative with increased potency (IC50 0.85 μM, 6-fold higher). Activity profiling compound demonstrated it reacts cysteines. We show here represents class RCIs, which undergo addition elimination reaction cysteines their target proteins. further reversibility catalyzed by exogenous thiols dependent size incoming thiol. contrast, traditional RCIs are all upon Michael mechanism base-catalyzed. identify introduces more reactive warhead pronounced selectivity profile thiol ligand size. This could allow expansion RCI modality use towards larger group proteins important human disease.

Language: Английский

Citations

5
Combinatorial Regimens Augment Drug Monotherapy for SARS-CoV-2 Clearance in Mice DOI Open Access
Irfan Ullah, Fanny Escudié, Ivan Scandale

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 1, 2023

Summary Direct acting antivirals (DAAs) represent critical tools for combating SARS-CoV-2 variants of concern (VOCs) that evolve to escape spike-based immunity and future coronaviruses with pandemic potential. Here, we used bioluminescence imaging evaluate therapeutic efficacy DAAs target RNA-dependent RNA polymerase (favipiravir, molnupiravir) or Main protease (nirmatrelvir) against Delta Omicron VOCs in K18-hACE2 mice. Nirmatrelvir displayed the best followed by molnupiravir favipiravir suppressing viral loads lung. Unlike neutralizing antibody treatment, DAA monotherapy did not eliminate However, targeting two enzymes combining nirmatrelvir resulted superior virus clearance. Furthermore, Caspase-1/4 inhibitor mitigated inflammation lung pathology whereas COVID-19 convalescent plasma yielded rapid clearance 100% survival. Thus, our study provides insights into treatment efficacies other effective combinations bolster arsenal.

Language: Английский

Citations

2