A low-background, fluorescent assay to evaluate inhibitors of diverse viral proteases DOI
R. Leonard, Rao Vn,

Alexandria Bartlett

et al.

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(8)

Published: Aug. 14, 2023

ABSTRACT Multiple coronaviruses (CoVs) can cause respiratory diseases in humans. While prophylactic vaccines designed to prevent infection are available for severe acute syndrome coronavirus-2 (SARS-CoV-2), incomplete vaccine efficacy, hesitancy, and the threat of other pathogenic CoVs which do not exist have highlighted need effective antiviral therapies. compounds targeting viral polymerase protease already clinical use, their sensitivity potential resistance mutations as well breadth against full range human preemergent remain incompletely defined. To begin fill that gap knowledge, we report here development an improved, noninfectious, cell-based fluorescent assay with high low background reports on activity proteases, key drug targets. We demonstrate is compatible only SARS-CoV-2 M pro protein but also orthologues from a nonhuman clinically reported drug-resistant variants. then use this define two used inhibitors, nirmatrelvir ensitrelvir. Continued will help strengths limitations current therapies may facilitate next-generation inhibitors broadly active both currently circulating CoVs. IMPORTANCE Coronaviruses important pathogens ability global pandemics. Working concert vaccines, antivirals specifically limit disease people who actively infected. Antiviral target CoV proteases use; efficacy variant zoonotic CoVs, however, remains Here, highly sensitive method defining small molecule inhibitors. approach mutants panel diverse proteases. Additionally, show system adaptable structurally nonrelated In future, be better develop new, acting more families.

Language: Английский

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 DOI Open Access
Lia Fiaschi,

Camilla Biba,

Ilenia Varasi

et al.

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

Citations

2
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 DOI Creative Commons
Lia Fiaschi,

Camilla Biba,

Ilenia Varasi

et al.

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

Citations

2
Real World Effectiveness of Tixagevimab/cilgavimab (Evusheld) in the Omicron Era DOI Creative Commons
Benjamin Chen, Nina M. Haste,

Nancy Binkin

et al.

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

Published: Sept. 17, 2022

Abstract Background Pre-exposure prophylaxis for COVID-19 with tixagevimab/cilgavimab (T/C) received Emergency Use Authorization (EUA) based off of results from a clinical trial conducted prior to the Omicron variant. Its effectiveness has not been well described in era. We examined incidence symptomatic illness and hospitalizations among T/C recipients when accounted virtually all cases. Methods used electronic medical record identify patients who at our institution. Among these patients, we assessed cases associated before after receiving T/C. chi square tests Fishers exact p-values examine differences between characteristics those got COVID prophylaxis. Results Of 1295 recipients, 121 (9.3%) developed T/C, 102 (7.9%) disease it. infection 36/121 (29.8%) were hospitalized, including 8 (6.6%) admitted ICU. 6/102 (5.9%) hospitalized but none required ICU admission. No COVID-related deaths occurred either group. The majority infected treatment during BA.1 surge, while post-T/C BA.5 was predominant. Patients had fewer vaccine doses less likely receive therapeutics compared having Conclusion identified infections persons eligible illnesses occurring require hospitalization In presence changing coverage, multiple therapies, variants, era remains difficult assess.

Language: Английский

Citations

9
Overview of Antiviral Drug Therapy for COVID-19: Where Do We Stand? DOI Creative Commons
Renata Esposito, Davida Mirra, Liberata Sportiello

et al.

Biomedicines, Journal Year: 2022, Volume and Issue: 10(11), P. 2815 - 2815

Published: Nov. 4, 2022

The vaccine weapon has resulted in being essential fighting the COVID-19 outbreak, but it is not fully preventing infection due to an alarming spreading of several identified variants concern. In fact, recent emergence pointed out how SARS-CoV-2 pandemic still represents a global health threat. Moreover, oral antivirals also develop resistance, supporting need find new targets as therapeutic tools. However, cocktail therapy useful reduce drug resistance and maximize vaccination efficacy. Natural products metal-drug-based treatments have shown interesting antiviral activity, representing valid contribution counter outbreak. This report summarizes available evidence which supports use approved drugs further focuses on significant clinical trials that investigated safety efficacy repurposing molecules different phenotypes. To date, there are many individuals vulnerable exhibiting severe symptoms, thus characterizing strategies for better management disease challenge.

Language: Английский

Citations

9
Switching the three-component Biginelli-like reaction conditions for the regioselective synthesis of new 2-amino[1,2,4]triazolo[1,5-a]pyrimidines DOI Creative Commons
Martina Pacetti, Maria Chiara Pismataro, Tommaso Felicetti

et al.

Organic & Biomolecular Chemistry, Journal Year: 2023, Volume and Issue: 22(4), P. 767 - 783

Published: Dec. 19, 2023

Facile procedures exploiting three-component reactions were developed to regioselectively obtain 2-amino-7-methyl-5-phenyl- and 2-amino-5-methyl-7-phenyl-[1,2,4]triazolo[1,5- a ]pyrimidine analogues bearing C-6 electron withdrawing group.

Language: Английский

Citations

4
Prevention and treatment strategies for kidney transplant recipients in the context of long-term existence of COVID-19 DOI Creative Commons
Zeyuan Zheng, Huimin Sun, Xiao Hu

et al.

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

Published: April 3, 2024

The sudden outbreak of coronavirus disease 2019 (COVID-19) in early 2020 posed a massive threat to human life and caused an economic upheaval worldwide. Kidney transplant recipients (KTRs) became susceptible infection during the COVID-19 pandemic owing their use immunosuppressants, resulting increased hospitalization mortality rates. Although current epidemic situation is alleviated, long-term existence still seriously threatens health KTRs with low immunity. Omicron variant, highly infectious but less-pathogenic strain severe acute respiratory syndrome 2 (SARS-CoV-2), has raised concerns among physicians regarding managing diagnosed this variant. However, currently, there are no clear unified guidelines for caring infected Therefore, we aimed summarize ongoing research on drugs that can treat variant infections explore potential adjusting immunotherapy strategies enhance responsiveness vaccines. Herein, discuss since emergence focus various prevention treatment outbreak. We hope assist presence variants.

Language: Английский

Citations

1
Liver tests abnormalities with licensed antiviral drugs for COVID-19: a narrative review DOI
Giacomo Casalini, Andrea Giacomelli, Spinello Antinori

et al.

Expert Opinion on Drug Safety, Journal Year: 2022, Volume and Issue: 21(12), P. 1483 - 1494

Published: Dec. 2, 2022

Introduction Liver involvement in COVID-19 is multifactorial, and the three potential mechanisms are direct hepatocyte viral damage, vascular or cellular damage during cytokine storm of severe drug-induced liver injury. To date, antivirals licensed for treatment by most guidelines: remdesivir, molnupiravir, ritonavir-boosted nirmatrelvir.Areas covered We performed a narrative review about hepatic safety profile treatment. used data hepatobiliary adverse events from English-language randomized clinical trials (RCTs).Expert opinion Remdesivir was found to be potentially hepatotoxic, biochemistry abnormalities were common (2–34%) but mild reversible. Molnupiravir exhibits favorable increase aminotransferases usually reversible (up 11% patients one study). Ritonavir-boosted nirmatrelvir only phase 3 RCT there no issues aspartate aminotransferase/alanine aminotransferase levels did not exceed 2.4% patients. All have profile, they sufficiently studied with underlying chronic kidney disease. In this special populations, should caution careful monitoring pursued on case-by-case basis.

Language: Английский

Citations

6
Real world effectiveness of sotrovimab in preventing COVID-19–related hospitalisation or death in patients infected with Omicron BA.2 DOI Creative Commons
Alwaleed Abdulaziz Behzad,

Aamal Mohamed,

Ahmed Ali

et al.

Journal of Infection and Public Health, Journal Year: 2023, Volume and Issue: 17(2), P. 315 - 320

Published: Dec. 4, 2023

Laboratory-based evidence indicates that neutralization of the BA.2 (Omicron) variant by sotrovimab is reduced versus previous SARS-CoV-2 variants. Since there a lack real-world data, we investigated whether has clinical efficacy against variant.

Language: Английский

Citations

3
Effectiveness of Sotrovimab in the Omicron Storm Time: A Case Series DOI Creative Commons

Gaetano Cicchitto,

Lorena Cardillo, Davide Sequino

et al.

Viruses, Journal Year: 2022, Volume and Issue: 15(1), P. 102 - 102

Published: Dec. 30, 2022

Neutralizing monoclonal antibodies (mAbs) for pre- and post-exposure prophylaxis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are largely used to prevent the progression disease by blocking viral attachment, host cell entry, infectivity. Sotrovimab, like other available mAbs, has been developed against receptor binding Domain Spike (S) glycoprotein virus. Nevertheless, latest Omicron variant shown marked mutations within S gene, thus opening question efficacy these neutralizing molecules towards this novel variant. In present observational study, we describe effects Sotrovimab in treatment 15 fully vaccinated patients, infected SARS-CoV-2 sub-variants, who were selected on basis factors widely considered affect a worse prognosis: immune suppression (n = 12) and/or chronic kidney 5) with evidence interstitial pneumonia nine patients. The effectiveness severe cases COVID-19 was demonstrated regression symptoms (mean 5.7 days), no need hospitalisation, improvement general health conditions clearance 30 days all conclusion, although loss or reduction mAbs activity have described, clinically proven be safe useful patients high risk sub-variants.

Language: Английский

Citations

3
A phase I/II study of adoptive SARS-CoV-2-specific T cells in immunocompromised hosts with or at risk of severe COVID-19 infection DOI Creative Commons
Michaela Su-Fern Seng, King Pan Ng,

Teck Guan Soh

et al.

Cytotherapy, Journal Year: 2024, Volume and Issue: 26(10), P. 1170 - 1178

Published: May 18, 2024

Post-transplant or hematological cancer patients have a higher risk of mortality after infection with ancestral and early variants severe acute respiratory syndrome (SARS)-CoV-2. Adoptive cell therapy (ACT) virus-specific T cells (VSTs) could augment endogenous immunity to avoid disease deterioration before viral clearance.

Language: Английский

Citations

0