Mechanism and spectrum of inhibition of a 4′-cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses DOI Creative Commons
Calvin J. Gordon, Simon Walker, Egor P. Tchesnokov

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(8), P. 107514 - 107514

Published: June 28, 2024

The development of safe and effective broad-spectrum antivirals that target the replication machinery respiratory viruses is high priority in pandemic preparedness programs. Here, we studied mechanism action a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRps) prototypic viruses. GS-646939 active 5'-triphosphate metabolite 4'-cyano modified C-adenosine phosphoramidate prodrug GS-7682. Enzyme kinetics show RdRps human rhinovirus type 16 (HRV-16) enterovirus 71 incorporate with unprecedented selectivity; incorporated 20-50-fold more efficiently than its natural ATP counterpart. RdRp complex syncytial virus metapneumovirus similar efficiency. In contrast, influenza B shows clear preference for mitochondrial polymerase does not significant incorporation GS-646939. Once into nascent strand, acts as chain terminator although higher NTP concentrations can partially overcome inhibition some polymerases. Modeling biochemical data suggest 4'-modification inhibits translocation. Comparative studies GS-443902, triphosphate form 1'-cyano prodrugs remdesivir obeldesivir, reveal only different mechanisms inhibition, but also differences spectrum viral conclusion, modifications analogs provide complementary strategies to several families

Language: Английский

Single-molecule assay reveals the impact of composition, RNA duplex, and inhibitors on the binding dynamics of SARS-CoV-2 polymerase complex DOI Creative Commons
Terri C. Lovell,

Heidi A. F. Dewling,

Cynthia X. Li

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

Abstract The genome replication of SARS-CoV-2, the causative agent COVID-19, involves a multi-subunit complex consisting non-structural proteins (nsps) 12, 7 and 8. While structure this is known, dynamic behavior subunits interacting with RNA missing. Here we report single-molecule protein-induced fluorescence enhancement (SM-PIFE) assay to monitor binding dynamics between reconstituted or co-expressed RNA. Increasing times were observed, in order, nsp7 (none) nsp8 nsp12, nsp8-nsp12 mixtures bearing all three proteins. Unstable, transient, stable modes recorded latter case, indicating that complexation dynamic, correct conformation must be achieved before can occur. Notably, protein yields mostly even at low concentrations, while exhibit unstable inefficient reduced protein. SM-PIFE distinguishes inhibitors impact from those prevent replication, as demonstrated suramin remdesivir, respectively. data reveals correlation lifetime/affinity, activity, underscores differences vs mixtures, suggesting existence trapped conformations may not evolve productive binding.

Language: Английский

Citations

0
Remdesivir and Obeldesivir Retain Potent Antiviral Activity Against SARS-CoV-2 Omicron Variants DOI Creative Commons

Lauren Rodriguez,

J. Lizbeth Reyes Zamora, Dong Han

et al.

Viruses, Journal Year: 2025, Volume and Issue: 17(2), P. 168 - 168

Published: Jan. 25, 2025

As new SARS-CoV-2 variants continue to emerge, it is important evaluate the potency of antiviral drugs support their continued use. Remdesivir (RDV; VEKLURY®) an approved treatment for COVID-19, and obeldesivir (ODV) are inhibitors RNA-dependent RNA polymerase Nsp12. Here we show these two compounds retain activity against Omicron BA.2.86, BF.7, BQ.1, CH.1.1, EG.1.2, EG.5.1, EG.5.1.4, FL.22, HK.3, HV.1, JN.1, JN.1.7, JN.1.18, KP.2, KP.3, LB.1, XBB.1.5, XBB.1.5.72, XBB.1.16, XBB.2.3.2, XBC.1.6, XBF when compared with reference strains. Genomic analysis identified 29 Nsp12 polymorphisms in previous variants. Phenotypic confirmed no impact on RDV or ODV suggests containing remain susceptible both compounds. These data use context circulating development as therapeutic.

Language: Английский

Citations

0
Covalent inhibition of the SARS-CoV-2 NiRAN domain via an active-site cysteine DOI Creative Commons
Genaro Hernandez, Adam Osinski, Abir Majumdar

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108378 - 108378

Published: March 1, 2025

Language: Английский

Citations

0
Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr DOI Creative Commons
Florian Kabinger,

Valerie Doze,

Jana Schmitzová

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(10)

Published: March 4, 2025

Targeting the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with small molecules is a promising therapeutic strategy against COVID-19, but potent and safe inhibitors are lacking. HeE1-2Tyr, nonnucleoside inhibitor Dengue virus RdRp, was also shown to inhibit RdRp in vitro have antiviral activity cells, underlying mechanism remains unclear. Here, we elucidate molecular HeE1-2Tyr-mediated inhibition. Biochemical assays confirm that HeE1-2Tyr inhibits an IC 50 5 µM show it competes binding vitro. Structural analysis using cryo-EM reveals stack three binds site RdRp. The identification conserved its intriguing inhibition stacked outcompete may facilitate further development pan-corona inhibitors.

Language: Английский

Citations

0
In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologs DOI

Shamiya Anwar Kizhakkiniyakath,

Tejaswini Choudhury,

Madhan Vishal Rajan

et al.

Biochemistry and Biophysics Reports, Journal Year: 2025, Volume and Issue: 42, P. 101975 - 101975

Published: March 13, 2025

Language: Английский

Citations

0
Identification of potent multi-target antiviral natural compounds from the fungal metabolites against aspartyl viral polymerases DOI Creative Commons

Zohreh Sahhaf Razavi,

Ali Ramazani,

Armin Zarei

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 13, 2025

Since viral polymerases are responsible for replication, they a prime target in antiviral drug development. The present study evaluated the potential of 174 secondary metabolites Sordariales order against aspartyl polymerases, including hepatitis C virus nonstructural protein 5B (HCV NS5B) and Severe acute respiratory syndrome coronavirus 2 RNA-dependent RNA polymerase (SARS CoV-2 RdRp). A two-step virtual screening was performed, identifying 76 ligands binding to active site, while 10 showed energies below -7 kcal/mol. Ligands 1–3 exhibited better affinities than Ribavirin. Lig-3 demonstrated most intense interaction. These interacted through hydrogen bonding hydrophobic interactions with key catalytic motifs that may disrupt replication by inhibiting activities. Next, effects these induced structure dynamics were analyzed 300 ns molecular (MD) simulations, showing ligand altered structural critical NTP template binding. RMSF PCA analyses revealed reduced mobility significant destabilization, particularly Lig-1 SARS-CoV-2 RdRp Lig-2 HCV NS5B. Additionally, Rg SASA indicated compression ligand-bound complexes, corroborating hypothesis enzymatic inhibition. MM/PBSA analysis highlighted as having stronger RdRp, displayed higher With promising ADME/T properties, is multi-target candidate NS5B meriting further vitro vivo investigations.

Language: Английский

Citations

0
Structural Biology of the SARS-CoV-2 replication–transcription complex DOI Creative Commons
Cameron D. Fyfe, Cromarte Rogers, Alexander Matthew Payne

et al.

Crystallography Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 20

Published: March 18, 2025

Language: Английский

Citations

0
A Multi-Model Machine Learning Framework for Identifying Raloxifene as a Novel RNA Polymerase Inhibitor from FDA-Approved Drugs DOI Creative Commons
Nhung Thi Hong Van,

Minh Tuan Nguyen

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(5), P. 315 - 315

Published: April 28, 2025

RNA-dependent RNA polymerase (RdRP) represents a critical target for antiviral drug development. We developed multi-model machine learning framework combining five traditional algorithms (ExtraTreesClassifier, RandomForestClassifier, LGBMClassifier, BernoulliNB, and BaggingClassifier) with CNN deep model to identify potential RdRP inhibitors among FDA-approved drugs. Using the PubChem dataset AID 588519, our ensemble models achieved highest performance accuracy, ROC-AUC, F1 scores higher than 0.70, while demonstrated complementary predictive value specificity of 0.77 on external validation. Molecular docking studies norovirus (PDB: 4NRT) identified raloxifene as promising candidate, binding affinity (−8.8 kcal/mol) comparable positive control (−9.2 kcal/mol). The molecular dynamics simulation confirmed stable RMSD values 0.12–0.15 nm protein–ligand complex consistent hydrogen bonding patterns. Our findings suggest that may possess inhibitory activity, providing foundation its experimental validation broad-spectrum agent.

Language: Английский

Citations

0
An Overview on Anti-COVID-19 Drug Achievements and Challenges Ahead DOI
Mehdi Valipour, Hamid Irannejad, Hossein Keyvani

et al.

ACS Pharmacology & Translational Science, Journal Year: 2023, Volume and Issue: 6(9), P. 1248 - 1265

Published: Aug. 16, 2023

The appearance of several coronavirus pandemics/epidemics during the last two decades (SARS-CoV-1 in 2002, MERS-CoV 2012, and SARS-CoV-2 2019) indicates that humanity will face increasing challenges from coronaviruses future. emergence new strains with similar transmission characteristics as mortality rates to SARS-CoV-1 (∼10% mortality) or (∼35% future is a terrifying possibility. Therefore, getting enough preparations such risks an inevitable necessity. present study aims review drug achievements fight against combined perspective derived pharmacology, pharmacotherapy, medicinal chemistry insights. Appreciating all efforts made past few years, there strong evidence desired results have not yet been achieved research this area should still be pursued seriously. By expressing some pessimistic possibilities concluding discovery pharmacotherapy COVID-19 successful so far, short essay tries draw attention responsible authorities more prepared epidemics/pandemics.

Language: Английский

Citations

9
Structural and functional insights into the enzymatic plasticity of the SARS-CoV-2 NiRAN domain DOI Creative Commons
Gabriel I. Small, Olga Fedorova, Paul Dominic B. Olinares

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(21), P. 3921 - 3930.e7

Published: Oct. 26, 2023

Language: Английский

Citations

9