SARS-CoV-2 Drug Resistance and Therapeutic Approaches

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

Published: Jan. 1, 2025

Language: Английский

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Ensitrelvir Fumaric Acid: First Approval

Drugs, Journal Year: 2024, Volume and Issue: 84(6), P. 721 - 728

Published: May 25, 2024

Language: Английский

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SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(4), P. 632 - 657

Published: April 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Language: Английский

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Non-peptidic inhibitors targeting SARS-CoV-2 main protease: A review

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107380 - 107380

Published: April 16, 2024

Language: Английский

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Computational evaluation and benchmark study of 342 crystallographic holo-structures of SARS-CoV-2 Mpro enzyme

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: June 20, 2024

Abstract The coronavirus disease 19 pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), has led to a global health crisis with millions of confirmed cases and related deaths. main protease (Mpro) SARS-CoV-2 is crucial for viral replication presents an attractive target drug development. Despite the approval some drugs, search effective treatments continues. In this study, we systematically evaluated 342 holo-crystal structures Mpro identify optimal conformations structure-based virtual screening (SBVS). Our analysis revealed limited structural flexibility among structures. Three docking programs, AutoDock Vina, rDock, Glide were employed assess efficiency screening, revealing diverse performances across selected We found that 5RHE, 7DDC, 7DPU (PDB Ids) consistently displayed lowest EF, AUC, BEDROCK scores. Furthermore, these demonstrated worst pose prediction results in all programs. Two differences contribute variations performance: absence S1 subsite 7DDC 7DPU, presence subpocket S2 5RHE. These findings underscore importance selecting appropriate SBVS, providing valuable insights advancing discovery efforts.

Language: Английский

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Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir

npj Viruses, Journal Year: 2024, Volume and Issue: 2(1)

Published: June 24, 2024

Abstract The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring ability efficiently spread among humans and become pandemic. Its high mortality rate of up 35% absence effective targeted therapies call for development antiviral drugs this pathogen. Since beginning SARS-CoV-2 pandemic, extensive research focused on identifying protease inhibitors treatment SARS-CoV-2. Our intention was therefore assess whether these are viable options combating MERS-CoV. To that end, we used previously established assays quantify inhibition SARS-CoV-2, main proteases. Nirmatrelvir inhibited several proteases, whereas ensitrelvir less broadly active. simulate nirmatrelvir’s clinical use against subsequent resistance development, applied a safe, surrogate virus-based system. Using virus, selected hallmark mutations SARS-CoV-2-M pro , such as T21I, M49L, S144A, E166A/K/V L167F. In current study, pool MERS-CoV-M mutants, characterized modelled steric effect catalytic site mutants S142G, S142R, S147Y A171S.

Language: Английский

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Identifying Natural Products as Feline Coronavirus M^pro Inhibitors by Structural-Based Virtual Screening and Enzyme-Based Assays

ACS Omega, Journal Year: 2025, Volume and Issue: 10(2), P. 2092 - 2101

Published: Jan. 10, 2025

The main protease (Mpro) is a pivotal target in the life cycle of feline coronavirus (FCoV), which causes high mortality disease, infectious peritonitis (FIP). Virtual screening was performed against Mpro to find active compounds with low toxicity from library natural products. Eighty-six were selected by using rank docking score and binding pose analysis. In enzyme-based assay, 12 showed more than 40% inhibitory effect on at concentration 200 μmol/L. IC50 values theaflavin 3,3′-digallate (25.0 μmol/L), sennoside C (25.2 pinocembrin-galloyl-HHDP-G (33.3 thonningianin A (50.6 μmol/L) determined. addition, curcuminoids (51.7–64.3% under flavonoids (41.3–60.3% also exhibited certain effects Mpro. Molecular dynamics simulations free energy calculations employed reveal atomic details these results that most formed significant interactions key residues catalytic site, such as His-41, Cys-144, Glu-165. These could serve starting point develop FCoV inhibitors potency.

Language: Английский

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Ensitrelvir treatment-emergent amino acid substitutions in SARS-CoV-2 3CLpro detected in the SCORPIO-SR phase 3 trial

Antiviral Research, Journal Year: 2025, Volume and Issue: unknown, P. 106097 - 106097

Published: Jan. 1, 2025

Language: Английский

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Antivirals in COVID‐19: A Focus on Pediatric Cardiac Patients

Canadian Journal of Infectious Diseases and Medical Microbiology, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

The COVID‐19 pandemic created an unprecedented public health crisis, driven by its rapid global spread and the urgent need for worldwide collaborative interventions to contain it. This urgency spurred search therapeutic agents prevent or manage infection. Among these, various types of antivirals emerged as a prominent treatment option, supported wealth observational studies randomized controlled trials. results from such conflict, with some concluding efficacy others lack thereof, variability also occurring depending on severity in studied population. In addition, many have been explored using trials—the gold standard evaluating intervention—to only limited degree, most evidence behind their use concluded studies. Thus, sheer volume data has made it challenging resolve inconsistencies determine true efficacy. Furthermore, there is paucity literature regarding pediatric population infected COVID‐19, being extrapolated done adult patients. As such, additional trials are needed solidify effectiveness managing particularly underexplored especially vulnerable cardiac Therefore, utilizing trials, this narrative review evaluates rationale antivirals, summarizes findings literature, concludes focused discussion application

Language: Английский

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Ensitrelvir as a novel treatment option for mild-to-moderate COVID-19: a narrative literature review

Therapeutic Advances in Infectious Disease, Journal Year: 2025, Volume and Issue: 12

Published: March 1, 2025

To address the coronavirus disease 2019 (COVID-19) pandemic, several antiviral agents targeting severe acute respiratory syndrome 2 (SARS-CoV-2) have been developed for clinical use. However, antivirals that can be administered irrespective of risk factors were lacking until approval ensitrelvir fumaric acid (hereafter, ensitrelvir) in Japan, which took effect November 2022. Ensitrelvir is an oral SARS-CoV-2 3C-like protease inhibitor currently approved Japan and Singapore. This narrative review summarizes preclinical, trial, real-world data on ensitrelvir. The efficacy safety assessed a seamless, randomized, double-blind, placebo-controlled, phase II/III study conducted South Korea, Vietnam (Japan Registry Clinical Trials identifier, jRCT2031210350). enrolled patients with mild-to-moderate COVID-19 symptoms or asymptomatic individuals presence illness. Overall, demonstrated favorable symptom improvement, acceptable profile. In III part, time to resolution composite five typical showed difference between 125 mg placebo groups, median was approximately 1 day when randomized less than 72 h onset. one trials used patient as endpoint. Additional are underway investigate various populations. Moreover, published evidence generally supports effectiveness routine practice its activity against variants concern. Further research granted establish novel treatment. Royalty-free licensing agreements concluded drug manufacturers Medicines Patent Pool will facilitate access therapeutics, including ensitrelvir, low- middle-income countries.

Language: Английский

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