1,2,3-Triazole-Benzofused Molecular Conjugates as Potential Antiviral Agents against SARS-CoV-2 Virus Variants

Life, Journal Year: 2022, Volume and Issue: 12(9), P. 1341 - 1341

Published: Aug. 29, 2022

SARS-CoV-2 and its variants, especially the Omicron variant, remain a great threat to human health. The need discover potent compounds that may control virus pandemic emerged mutants is rising. A set of 1,2,3-triazole and/or 1,2,4-triazole was synthesized either from benzimidazole or isatin precursors. Molecular docking studies in vitro enzyme activity revealed most investigated demonstrated promising binding scores against spike proteins, comparison reference drugs. In particular, compound 9 has highest scoring affinity proteins with IC50 reaching 75.98 nM protein 74.51 protein. possible interaction between triazoles viral by prevention entry into host cells, which led reduction reproduction infection. cytopathic inhibition assay airway epithelial cell line (Vero E6) infected effectiveness safety (compound 9) (EC50 CC50 reached 80.4 1028.28 µg/mL, respectively, selectivity index 12.78). Moreover, antiinflammatory effect tested pave way reduce reported SARS-CoV-2-induced hyperinflammation.

Language: Английский

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Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(17), P. 11701 - 11717

Published: Aug. 19, 2023

Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming bioactive triphosphate 2-NTP. 2-NTP, analog ATP, inhibits SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription viral RNA. Strong clinical results for have prompted interest in oral approaches to generate Here, we describe discovery a 5′-isobutyryl ester 2 (GS-5245, Obeldesivir, 3) has low cellular cytotoxicity 3–7-fold improved delivery monkeys. Prodrug 3 cleaved presystemically provide high systemic exposures overcome its less efficient metabolism leading strong antiviral efficacy African green monkey infection model. Exposure-based relationships resulted estimated dose 350–400 mg twice daily. Importantly, all variants remain susceptible 2, which supports development as promising COVID-19 treatment.

Language: Английский

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Determinants and Mechanisms of the Low Fusogenicity and High Dependence on Endosomal Entry of Omicron Subvariants

mBio, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 10, 2023

Omicron has been shown to predominantly use the endosomal entry pathway, resulting in reduced lung tropism and disease severity; however, underlying mechanism is not fully understood. In addition, whether most recent subvariants, including BA.5 BA.2.75, same pathway as their ancestor for currently known.

Language: Английский

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SARS-CoV-2 variants with NSP12 P323L/G671S mutations display enhanced virus replication in ferret upper airways and higher transmissibility

Cell Reports, Journal Year: 2023, Volume and Issue: 42(9), P. 113077 - 113077

Published: Sept. 1, 2023

With the emergence of multiple predominant SARS-CoV-2 variants, it becomes important to have a comprehensive assessment their viral fitness and transmissibility. Here, we demonstrate that natural temperature differences between upper (33°C) lower (37°C) respiratory tract profound effects on replication Specifically, variants containing NSP12 mutations P323L or P323L/G671S exhibit enhanced RNA-dependent RNA polymerase (RdRp) activity at 33°C compared with 37°C high Molecular dynamics simulations microscale thermophoresis stabilize NSP12-NSP7-NSP8 complex through hydrophobic effects, leading increased RdRp activity. Furthermore, competitive transmissibility assay reveals reverse genetic (RG)-P323L RG-P323L/G671S outcompetes RG-WT (wild-type) for in tract, allowing markedly rapid This suggests mutation is associated stability enzymatic activity, promoting efficient

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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Comprehensive Review of COVID-19: Epidemiology, Pathogenesis, Advancement in Diagnostic and Detection Techniques, and Post-Pandemic Treatment Strategies

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(15), P. 8155 - 8155

Published: July 26, 2024

At present, COVID-19 remains a public health concern due to the ongoing evolution of SARS-CoV-2 and its prevalence in particular countries. This paper provides an updated overview epidemiology pathogenesis COVID-19, with focus on emergence variants phenomenon known as ‘long COVID’. Meanwhile, diagnostic detection advances will be mentioned. Though many inventions have been made combat pandemic, some outstanding ones include multiplex RT-PCR, which can used for accurate diagnosis infection. ELISA-based antigen tests also appear potential tools available future. discusses current treatments, vaccination strategies, well emerging cell-based therapies The underscores necessity us continuously update scientific understanding treatments it.

Language: Английский

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Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics

Molecular Aspects of Medicine, Journal Year: 2022, Volume and Issue: 91, P. 101151 - 101151

Published: Oct. 28, 2022

With more than 5 million fatalities and close to 300 reported cases, COVID-19 is the first documented pandemic due a coronavirus that continues be major health challenge. Despite being rapid, uncontrollable, highly infectious in its spread, it also created incentives for technology development redefined public needs research agendas fast-track innovations translated. Breakthroughs computational biology peaked during with renewed attention making all cutting-edge deliver agents combat disease. The demand develop effective treatments yielded surprising collaborations from previously segregated fields of science technology. long-standing pharmaceutical industry's aversion repurposing existing drugs lack exponential financial gain was overrun by crisis pressures front-line researchers providers. Effective vaccine even at an unprecedented pace took year commence trials. Now emergence variants waning protections booster shots resulting breakthrough infections continue strain care systems. As now, every protein SARS-CoV-2 has been structurally characterized related host pathways have extensively mapped out. community addressed druggability multitude possible targets. This made virtual computer-assisted drug as well new tools technologies such artificial intelligence leads. Here this article, we are discussing advances discovery field target-based exploring implications known target-specific on therapeutic management. current scenario calls personalized medicine efforts stratifying patient populations early their need different combinations prognosis-specific therapeutics. We intend highlight target hotspots potential agents, ultimate goal using rational design therapeutics not only end but uncover generalizable platform use future pandemics.

Language: Английский

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In Vitro Selection of Remdesivir-Resistant SARS-CoV-2 Demonstrates High Barrier to Resistance

Antimicrobial Agents and Chemotherapy, Journal Year: 2022, Volume and Issue: 66(7)

Published: June 16, 2022

In vitro selection of remdesivir-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed the emergence a V166L substitution, located outside polymerase active site Nsp12 protein, after 9 passages single lineage. remained only substitution 17 (10 μM remdesivir), conferring 2.3-fold increase in 50% effective concentration (EC 50 ).

Language: Английский

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Evaluation of antiviral drugs against newly emerged SARS-CoV-2 Omicron subvariants

Antiviral Research, Journal Year: 2023, Volume and Issue: 214, P. 105609 - 105609

Published: April 20, 2023

Language: Английский

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Viral Resistance Analyses From the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1)

The Journal of Infectious Diseases, Journal Year: 2023, Volume and Issue: 228(9), P. 1263 - 1273

Published: July 19, 2023

Abstract Background Remdesivir is approved for treatment of coronavirus disease 2019 (COVID-19) in nonhospitalized and hospitalized adult pediatric patients. Here we present severe acute respiratory syndrome 2 (SARS-CoV-2) resistance analyses from the phase 3 ACTT-1 randomized placebo-controlled trial conducted participants with COVID-19. Methods Swab samples were collected at baseline longitudinally through day 29. SARS-CoV-2 genomes sequenced using next-generation sequencing. Phenotypic analysis was directly on participant virus isolates and/or subgenomic replicons expressing mutations identified Nsp12 target gene. Results Among both postbaseline sequencing data, emergent substitutions observed 12 31 (38.7%) 30 (40.0%) remdesivir placebo arms, respectively. No arm more than 1 participant. Phenotyping showed low to no change susceptibility relative wild-type reference tested: A16V (0.8-fold EC50), P323L + V792I (2.2-fold), C799F (2.5-fold), K59N (1.0-fold), (3.4-fold). Conclusions The similar rate emerging arms minimal among tested support a high barrier development COVID-19 Clinical Trials Registration. NCT04280705.

Language: Английский

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