Deep mining of the Sequence Read Archive reveals major genetic innovations in coronaviruses and other nidoviruses of aquatic vertebrates DOI Creative Commons
Chris Lauber, Xiaoyu Zhang,

Josef Vaas

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(4), P. e1012163 - e1012163

Published: April 22, 2024

Virus discovery by genomics and metagenomics empowered studies of viromes, facilitated characterization pathogen epidemiology, redefined our understanding the natural genetic diversity viruses with profound functional structural implications. Here we employed a data-driven virus approach that directly queries unprocessed sequencing data in highly parallelized way involves targeted viral genome assembly strategy wide range sequence similarity. By screening more than 269,000 datasets numerous authors from Sequence Read Archive using two metrics quantitatively assess quality, discovered 40 nidoviruses six families whose members infect vertebrate hosts. They form 13 32 putative subfamilies genera, respectively, include 11 coronaviruses bisegmented genomes fishes amphibians, giant 36.1 kilobase coronavirus duplicated spike glycoprotein (S) gene, tobaniviruses 17 additional corona-, arteri-, cremega-, nanhypo- nangoshaviruses. Genome segmentation emerged single evolutionary event monophyletic lineage encompassing subfamily Pitovirinae . We recovered sequences RNA samples 69 infected validated presence poly(A) tails at both segments 3’RACE PCR subsequent Sanger sequencing. report linkage between accessory proteins phylogenetic relationships distances are incongruent phylogeny replicase proteins. rationalize these observations model inter-family S recombination involving least five ancestral corona- aquatic In support this model, describe an individual fish co-infected Coronaviridae Tobaniviridae Our results expand scale known extraordinary plasticity nidoviral architecture call for revisiting fundamentals expression, particle biology, host ecology nidoviruses.

Language: Английский

Therapeutic strategies for COVID-19: progress and lessons learned DOI Open Access
Guangdi Li, Rolf Hilgenfeld, Richard J. Whitley

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 449 - 475

Published: April 19, 2023

Language: Английский

Citations

420
Accelerating antiviral drug discovery: lessons from COVID-19 DOI Open Access
Annette von Delft, Matthew D. Hall, Ann D. Kwong

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(7), P. 585 - 603

Published: May 12, 2023

Language: Английский

Citations

100
The mechanism of RNA capping by SARS-CoV-2 DOI Creative Commons
Gina J. Park, Adam Osinski, Genaro Hernandez

et al.

Nature, Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 9, 2022

The RNA genome of SARS-CoV-2 contains a 5' cap that facilitates the translation viral proteins, protection from exonucleases and evasion host immune response1-4. How this is made in not completely understood. Here we reconstitute N7- 2'-O-methylated (7MeGpppA2'-O-Me) using virally encoded non-structural proteins (nsps). We show kinase-like nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain5 nsp12 transfers to amino terminus nsp9, forming covalent RNA-protein intermediate (a process termed RNAylation). Subsequently, NiRAN domain GDP, core structure GpppA-RNA. nsp146 nsp167 methyltransferases then add methyl groups form functional structures. Structural analyses replication-transcription complex bound nsp9 identified key interactions mediate capping reaction. Furthermore, demonstrate reverse genetics system8 N active-site residues are required for successful replication. Collectively, our results reveal an unconventional mechanism by which caps its genome, thus exposing new target development antivirals treat COVID-19.

Language: Английский

Citations

90
SARS-CoV-2 biology and host interactions DOI
Silvio Steiner, Annika Kratzel, G. Tuba Barut

et al.

Nature Reviews Microbiology, Journal Year: 2024, Volume and Issue: 22(4), P. 206 - 225

Published: Jan. 15, 2024

Language: Английский

Citations

83
Small molecules in the treatment of COVID-19 DOI Creative Commons
Sibei Lei, Xiaohua Chen, Jieping Wu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Language: Английский

Citations

82
Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China DOI Open Access
Liyan Yang, Zhonglei Wang

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 257, P. 115503 - 115503

Published: May 18, 2023

Language: Английский

Citations

64
Novel Investigational Anti-SARS-CoV-2 Agent Ensitrelvir “S-217622”: A Very Promising Potential Universal Broad-Spectrum Antiviral at the Therapeutic Frontline of Coronavirus Species DOI Creative Commons
Wafa Ali Eltayb, Mohnad Abdalla, Amgad M. Rabie

et al.

ACS Omega, Journal Year: 2023, Volume and Issue: 8(6), P. 5234 - 5246

Published: Jan. 30, 2023

Lately, nitrogenous heterocyclic antivirals, such as nucleoside-like compounds, oxadiazoles, thiadiazoles, triazoles, quinolines, and isoquinolines, topped the therapeutic scene promising agents of choice for treatment severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections their accompanying ailment, disease 2019 (COVID-19). At same time, continuous emergence new strains SARS-CoV-2, like Omicron variant its multiple sublineages, resulted in a defiance enduring COVID-19 battle. Ensitrelvir (S-217622) is newly discovered orally active noncovalent nonpeptidic agent with potential strong broad-spectrum anticoronaviral activities, exhibiting nanomolar potencies against different SARS-CoV-2 variants. S-217622 effectively nonspecifically hits main protease (Mpro) enzyme broad scope coronaviruses. Herein, present computational/biological study, we tried to extend these previous findings prove universal activities this investigational any coronavirus, irrespective type, through synchronously acting on most unchanged replication enzymes/proteins, including (in addition Mpro), e.g., highly conserved RNA-dependent RNA polymerase (RdRp) 3'-to-5' exoribonuclease (ExoN). Biochemical evaluation proved, using vitro anti-RdRp/ExoN bioassay, that can potently inhibit coronaviruses, virulent extremely minute anti-RdRp half-maximal effective concentration (EC50) values 0.17 0.27 μM, respectively, transcending anti-COVID-19 drug molnupiravir. The preliminary silico results greatly supported biochemical results, proposing molecule strongly stabilizingly strikes key catalytic pockets RdRp's ExoN's principal sites predictably via nucleoside analogism mode anti-RNA action (since be considered uridine analog). Moreover, idealistic druglikeness pharmacokinetic characteristics make it ready pharmaceutical formulation expected very good clinical behavior caused by COVID-19. To cut short, current critical extension work significantly potentiate S-217622's vitro/in vivo (preclinical) since they showed striking inhibitory novel anti-SARS-CoV-2 Mpro could extended other enzymes RdRp ExoN, unveiling possible use compound next versions virus (i.e., disclosing nonspecific properties almost strain), SARS-CoV-3, encouraging us rapidly start compound's vast evaluations.

Language: Английский

Citations

51
Structural basis for substrate selection by the SARS-CoV-2 replicase DOI Open Access
Brandon Malone, Jason K. Perry, Paul Dominic B. Olinares

et al.

Nature, Journal Year: 2023, Volume and Issue: 614(7949), P. 781 - 787

Published: Feb. 1, 2023

Language: Английский

Citations

48
Chemical-guided SHAPE sequencing (cgSHAPE-seq) informs the binding site of RNA-degrading chimeras targeting SARS-CoV-2 5’ untranslated region DOI Creative Commons
Zhichao Tang,

Shalakha Hegde,

Siyuan Hao

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 8, 2025

One of the hallmarks RNA viruses is highly structured untranslated regions (UTRs) which are often essential for viral replication, transcription, or translation. In this report, we discovered a series coumarin derivatives that bind to four-way helix called SL5 in 5' UTR SARS-CoV-2 genome. To locate binding site, developed sequencing-based method namely cgSHAPE-seq, an acylating probe was directed crosslink with 2'-OH group ribose at site create read-through mutations during reverse transcription. cgSHAPE-seq unambiguously determined bulged G as primary validated through mutagenesis and vitro experiments. The were further used warhead designing RNA-degrading chimeras reduce expression levels. optimized chimera C64 inhibited live virus replication lung epithelial carcinoma cells. Highly serve potential drug targets. Here authors identified class small molecules Using they pinpointed inhibit replication.

Language: Английский

Citations

2
Sensitivity to Vaccines, Therapeutic Antibodies, and Viral Entry Inhibitors and Advances To Counter the SARS-CoV-2 Omicron Variant DOI
Hao Zhou, Michelle Møhlenberg,

Jigarji Chaturji Thakor

et al.

Clinical Microbiology Reviews, Journal Year: 2022, Volume and Issue: 35(3)

Published: June 6, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps evolving and mutating into newer variants over time, which gain higher transmissibility, disease severity, spread in communities at a faster rate, resulting multiple waves of surge Coronavirus Disease 2019 (COVID-19) cases. A highly mutated transmissible SARS-CoV-2 Omicron variant has recently emerged, driving the extremely high peak infections almost all continents an unprecedented speed scale. The evades protection rendered by vaccine-induced antibodies natural infection, as well overpowers antibody-based immunotherapies, raising concerns current effectiveness available vaccines monoclonal therapies. This review outlines most recent advancements studying virology biology variant, highlighting its increased resistance to therapeutics immune escape against vaccines. However, is sensitive viral fusion inhibitors targeting HR1 motif spike protein, enzyme inhibitors, involving endosomal pathway, ACE2-based entry inhibitors. variant-associated infectivity mechanisms are essentially distinct from previous characterized variants. Innate sensing evasion T cell immunity virus provide new perspectives vaccine drug development. These findings important for understanding advances developing vaccines, therapies, more effective strategies mitigate transmission or next concern.

Language: Английский

Citations

68