In addition to the spike mutations, this sequence also has ORF3a:A110V, ORF9b:A11V, ORF1b:P1727S, & ORF1b:G2662D.
One paper found that ORF1b:P1727L, which is in the proofreading NSP14 protein (NSP14:P203L), doubled mutation rates in hamsters. Would P203S (ORF1b:P1727S) have the same effect? 5/6
One paper found that ORF1b:P1727L, which is in the proofreading NSP14 protein (NSP14:P203L), doubled mutation rates in hamsters. Would P203S (ORF1b:P1727S) have the same effect? 5/6
October 13, 2025 at 12:04 PM
In addition to the spike mutations, this sequence also has ORF3a:A110V, ORF9b:A11V, ORF1b:P1727S, & ORF1b:G2662D.
One paper found that ORF1b:P1727L, which is in the proofreading NSP14 protein (NSP14:P203L), doubled mutation rates in hamsters. Would P203S (ORF1b:P1727S) have the same effect? 5/6
One paper found that ORF1b:P1727L, which is in the proofreading NSP14 protein (NSP14:P203L), doubled mutation rates in hamsters. Would P203S (ORF1b:P1727S) have the same effect? 5/6
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
a small molecule that can stop SARS-CoV-2 from replicating in cells. #immunologySky #MedSky
www.nature.com/artic...
1/5
a small molecule that can stop SARS-CoV-2 from replicating in cells. #immunologySky #MedSky
www.nature.com/artic...
1/5
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
Nature - The development of a first-in-class non-covalent small-molecule inhibitor of SARS-CoV-2 replication that targets the viral guanine-N7 methyltransferase NSP14 is reported.
www.nature.com
December 20, 2024 at 2:28 PM
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
a small molecule that can stop SARS-CoV-2 from replicating in cells. #immunologySky #MedSky
www.nature.com/artic...
1/5
a small molecule that can stop SARS-CoV-2 from replicating in cells. #immunologySky #MedSky
www.nature.com/artic...
1/5
#MedSky🧪 #IDSky #drugdevelopment #Pharmasky #SkyRx This study identified uncharged, #noncovalent inhibitors of #SARSCoV2 NSP14 MTase with picomolar affinity & slow dissociation kinetics that bind to the viral cap
rdcu.be/d3BkN
rdcu.be/d3BkN
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
Nature - The development of a first-in-class non-covalent small-molecule inhibitor of SARS-CoV-2 replication that targets the viral guanine-N7 methyltransferase NSP14 is reported.
rdcu.be
December 15, 2024 at 7:29 AM
#MedSky🧪 #IDSky #drugdevelopment #Pharmasky #SkyRx This study identified uncharged, #noncovalent inhibitors of #SARSCoV2 NSP14 MTase with picomolar affinity & slow dissociation kinetics that bind to the viral cap
rdcu.be/d3BkN
rdcu.be/d3BkN
SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation
www.nature.com/articles/s41...
www.nature.com/articles/s41...
SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation - Nature Communications
C10, a potent non-nucleoside inhibitor targeting NSP14’s SAM-binding pocket, suppresses viral translation, exhibits immunostimulatory effects, and reverses NSP14-induced transcriptome alterations, off...
www.nature.com
November 3, 2025 at 1:35 PM
SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation
www.nature.com/articles/s41...
www.nature.com/articles/s41...
One interesting (and possibly coincidental) observation on the BA.3.2 tree: Two large branches have NSP14 mutations at adjacent AA residues—ORF1b:T1896I and ORF1b:H1897Y. 2/4
December 9, 2025 at 12:09 PM
One interesting (and possibly coincidental) observation on the BA.3.2 tree: Two large branches have NSP14 mutations at adjacent AA residues—ORF1b:T1896I and ORF1b:H1897Y. 2/4
Zhejiang University researchers identified a compound called C10 that potently blocks SARS-CoV-2 by targeting a viral enzyme called NSP14.
In mice, C10 reduced virus levels and reversed virus-driven host cell damage.
www.nature.com/articles/s41...
In mice, C10 reduced virus levels and reversed virus-driven host cell damage.
www.nature.com/articles/s41...
SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation - Nature Communications
C10, a potent non-nucleoside inhibitor targeting NSP14’s SAM-binding pocket, suppresses viral translation, exhibits immunostimulatory effects, and reverses NSP14-induced transcriptome alterations, off...
www.nature.com
November 3, 2025 at 4:47 PM
Zhejiang University researchers identified a compound called C10 that potently blocks SARS-CoV-2 by targeting a viral enzyme called NSP14.
In mice, C10 reduced virus levels and reversed virus-driven host cell damage.
www.nature.com/articles/s41...
In mice, C10 reduced virus levels and reversed virus-driven host cell damage.
www.nature.com/articles/s41...
"Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase"
www.nature.com/articles/s41....
www.nature.com/articles/s41....
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase - Nature
The development of a first-in-class non-covalent small-molecule inhibitor of SARS-CoV-2 replication that targets the viral guanine-N7 methyltransferase NSP14 is reported.
www.nature.com
December 13, 2024 at 12:58 PM
"Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase"
www.nature.com/articles/s41....
www.nature.com/articles/s41....
Our new preprint on #SARSCoV2 nsp14 #exonuclease function in replication fidelity and fitness. ExoN- viruses are attenuated in vitro and in vivo but w/o #interferon signaling replication is largely restored! Suggests nsp14 plays a role in innate antagonism in vivo www.biorxiv.org/content/10.6...
Loss of nsp14-exonuclease activity impairs the replication, proofreading, fitness and pathogenesis of SARS-CoV-2
Coronaviruses (CoVs) replicate their RNA genomes with increased fidelity than other RNA viruses, a mechanism mediated by the proofreading and recombination activities of the exoribonuclease domain of ...
www.biorxiv.org
January 14, 2026 at 5:23 PM
Our new preprint on #SARSCoV2 nsp14 #exonuclease function in replication fidelity and fitness. ExoN- viruses are attenuated in vitro and in vivo but w/o #interferon signaling replication is largely restored! Suggests nsp14 plays a role in innate antagonism in vivo www.biorxiv.org/content/10.6...
Decoding the Attenuation:
How OMICRON BA.1's MUTATIONS in NSP14, ENVELOPE, and MEMBRANE Proteins MITIGATE NEUROPATHOGENICITY in Transgenic Mice
https://buff.ly/3W4rYxB
How OMICRON BA.1's MUTATIONS in NSP14, ENVELOPE, and MEMBRANE Proteins MITIGATE NEUROPATHOGENICITY in Transgenic Mice
https://buff.ly/3W4rYxB
January 4, 2025 at 4:34 AM
Decoding the Attenuation:
How OMICRON BA.1's MUTATIONS in NSP14, ENVELOPE, and MEMBRANE Proteins MITIGATE NEUROPATHOGENICITY in Transgenic Mice
https://buff.ly/3W4rYxB
How OMICRON BA.1's MUTATIONS in NSP14, ENVELOPE, and MEMBRANE Proteins MITIGATE NEUROPATHOGENICITY in Transgenic Mice
https://buff.ly/3W4rYxB
Zhejiang and Fudan University scientists identified C10, a first-in-class NSP14 inhibitor.
It blocked SARS-CoV-2 replication as potently as remdesivir, reversed virus-induced host changes, and protected infected mice, making it a promising antiviral.
www.biorxiv.org/content/10.1...
It blocked SARS-CoV-2 replication as potently as remdesivir, reversed virus-induced host changes, and protected infected mice, making it a promising antiviral.
www.biorxiv.org/content/10.1...
SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation
The emergence of SARS-CoV-2 variants and drug-resistant mutants highlights the urgent need for novel antiviral therapeutics. SARS-CoV-2 NSP14, an N7-guanosine methyltransferase, plays a critical role ...
www.biorxiv.org
August 26, 2025 at 12:46 PM
Zhejiang and Fudan University scientists identified C10, a first-in-class NSP14 inhibitor.
It blocked SARS-CoV-2 replication as potently as remdesivir, reversed virus-induced host changes, and protected infected mice, making it a promising antiviral.
www.biorxiv.org/content/10.1...
It blocked SARS-CoV-2 replication as potently as remdesivir, reversed virus-induced host changes, and protected infected mice, making it a promising antiviral.
www.biorxiv.org/content/10.1...
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase - Nature
The development of a first-in-class non-covalent small-molecule inhibitor of SARS-CoV-2 replication that targets the viral guanine-N7 methyltransferase NSP14 is reported.
www.nature.com
December 12, 2024 at 5:08 PM
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase
www.nature.com/articles/s41...
www.nature.com/articles/s41...
Targeting #Nsp14 as a promising pan-coronavirus strategy. 🧪
Scientists report a small molecule that can stop SARS-CoV-2—the virus that causes COVID-19—from replicating in cells and in mice by blocking an enzyme that hasn’t received much attention in antiviral efforts. cen.acs.org/pharmaceutic... #chemsky #bluesci 🧪 #scinews #biosky
A new way to take down SARS-CoV-2
Small molecule’s target is similar in many coronaviruses
cen.acs.org
December 20, 2024 at 1:22 PM
Targeting #Nsp14 as a promising pan-coronavirus strategy. 🧪
UNC and Vanderbilt researchers found that disabling SARS-CoV-2’s nsp14 proofreading enzyme makes the virus viable but weak, less accurate, less fit, and far less able to cause disease.
journals.asm.org/doi/10.1128/...
journals.asm.org/doi/10.1128/...
Loss of nsp14-exonuclease activity impairs the replication, proofreading, fitness, and pathogenesis of SARS-CoV-2 | mBio
Coronaviruses (CoV) are important human pathogens causing hundreds of millions of
infections and millions of deaths over the past 20 years. The study of how these viruses
multiply and cause disease id...
journals.asm.org
May 7, 2026 at 1:11 AM
UNC and Vanderbilt researchers found that disabling SARS-CoV-2’s nsp14 proofreading enzyme makes the virus viable but weak, less accurate, less fit, and far less able to cause disease.
journals.asm.org/doi/10.1128/...
journals.asm.org/doi/10.1128/...
SARS-CoV-2’s protein Nsp14 activates inflammatory pathways like NF-κB and MAPK, while suppressing interferon defenses (IFNAR1 and IFNGR1).
This dual action helps the virus evade immune responses and worsen inflammation.
www.biorxiv.org/content/10.1...
This dual action helps the virus evade immune responses and worsen inflammation.
www.biorxiv.org/content/10.1...
SARS-CoV-2 Nsp14 binds Tollip and activates pro-inflammatory pathways while downregulating interferon alpha and interferon gamma receptors
SARS coronavirus 2 (SARS-CoV-2) non-structural protein 14 (Nsp14) possesses an N-terminal exonuclease (ExoN) domain that provides a proofreading function for the viral RNA-dependent RNA polymerase and...
www.biorxiv.org
December 15, 2024 at 3:10 PM
SARS-CoV-2’s protein Nsp14 activates inflammatory pathways like NF-κB and MAPK, while suppressing interferon defenses (IFNAR1 and IFNGR1).
This dual action helps the virus evade immune responses and worsen inflammation.
www.biorxiv.org/content/10.1...
This dual action helps the virus evade immune responses and worsen inflammation.
www.biorxiv.org/content/10.1...
SARS-CoV-2 without proofreading are sad and weak viruses. out now in #mBio #lovevirology journals.asm.org/doi/10.1128/...
Loss of nsp14-exonuclease activity impairs the replication, proofreading, fitness, and pathogenesis of SARS-CoV-2 | mBio
Coronaviruses (CoV) are important human pathogens causing hundreds of millions of
infections and millions of deaths over the past 20 years. The study of how these viruses
multiply and cause disease id...
journals.asm.org
May 7, 2026 at 12:45 AM
SARS-CoV-2 without proofreading are sad and weak viruses. out now in #mBio #lovevirology journals.asm.org/doi/10.1128/...
Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase https://www.biorxiv.org/content/10.1101/2025.09.30.679521v1
October 2, 2025 at 3:46 AM
Crystallographic characterisation and development of bi-substrate inhibitors of coronavirus nsp14 methyltransferase https://www.biorxiv.org/content/10.1101/2025.09.30.679521v1
SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation https://www.biorxiv.org/content/10.1101/2025.08.21.671674v1
August 26, 2025 at 3:17 AM
SARS-CoV-2 NSP14 inhibitor exhibits potent antiviral activity and reverses NSP14-driven host modulation https://www.biorxiv.org/content/10.1101/2025.08.21.671674v1
#research #SARSCoV2 #nsp14
Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides (Nencka) - RSC? doi.org/10.1039/D4MD...
@iocbprague.bsky.social #NIVBcz #czechacademyofsciences #VSCHT #charlesuniversity
Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides (Nencka) - RSC? doi.org/10.1039/D4MD...
@iocbprague.bsky.social #NIVBcz #czechacademyofsciences #VSCHT #charlesuniversity
Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides
The emergence of SARS-CoV-2, the causative agent of COVID-19, has highlighted the need for advanced antiviral strategies. Targeting the coronaviral methyltransferase nsp14, which is essential for RNA ...
doi.org
September 13, 2024 at 8:55 AM
#research #SARSCoV2 #nsp14
Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides (Nencka) - RSC? doi.org/10.1039/D4MD...
@iocbprague.bsky.social #NIVBcz #czechacademyofsciences #VSCHT #charlesuniversity
Discovery of highly potent SARS-CoV-2 nsp14 methyltransferase inhibitors based on adenosine 5′-carboxamides (Nencka) - RSC? doi.org/10.1039/D4MD...
@iocbprague.bsky.social #NIVBcz #czechacademyofsciences #VSCHT #charlesuniversity
Mount Sinai researchers show that SARS-CoV-2 protein Nsp14 binds Tollip to drive inflammation while degrading interferon receptors, blocking key antiviral defenses and tilting the immune balance toward viral survival.
journals.asm.org/doi/10.1128/...
journals.asm.org/doi/10.1128/...
SARS-CoV-2 Nsp14 binds Tollip and activates pro-inflammatory pathways while downregulating interferon-α and interferon-γ receptors | mBio
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 14 (Nsp14) both activates NF-κB, which promotes virus replication and inflammation, and downregulates interferon alpha/beta receptor 1 (IFNAR1), which can render infected ...
journals.asm.org
June 25, 2025 at 4:55 PM
Mount Sinai researchers show that SARS-CoV-2 protein Nsp14 binds Tollip to drive inflammation while degrading interferon receptors, blocking key antiviral defenses and tilting the immune balance toward viral survival.
journals.asm.org/doi/10.1128/...
journals.asm.org/doi/10.1128/...
New research targets SARS-CoV-2 NSP14, an RNA cap methyltransferase, showing potential for novel antivirals. Engage for details! PMID:39663451, Nature 2025, @Nature https://doi.org/10.1038/s41586-024-08320-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase | Nature
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. The rapid development of highly effective vaccines2,3 against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics4 have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity5. Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant (Kd) of 61 pM and a half-maximal effective con
doi.org
March 30, 2025 at 10:00 PM
From 3,252 SARS-CoV-2 genomes to zero recurrent mutations.
That’s where my latest independent research landed after weeks of alignment, cleaning, filtering, and mutation calling across nsp7, nsp8, nsp12, and nsp14 .
LINK:
doi.org/10.6084/m9.f...
That’s where my latest independent research landed after weeks of alignment, cleaning, filtering, and mutation calling across nsp7, nsp8, nsp12, and nsp14 .
LINK:
doi.org/10.6084/m9.f...
May 24, 2025 at 7:36 AM
From 3,252 SARS-CoV-2 genomes to zero recurrent mutations.
That’s where my latest independent research landed after weeks of alignment, cleaning, filtering, and mutation calling across nsp7, nsp8, nsp12, and nsp14 .
LINK:
doi.org/10.6084/m9.f...
That’s where my latest independent research landed after weeks of alignment, cleaning, filtering, and mutation calling across nsp7, nsp8, nsp12, and nsp14 .
LINK:
doi.org/10.6084/m9.f...
A new study from Rockefeller University developed TDI-015051, a potent antiviral targeting SARS-CoV-2’s NSP14 protein.
It inhibits viral replication in cells and mice with efficacy similar to current treatments, showing promise for fighting COVID-19.
www.nature.com/articles/s41...
It inhibits viral replication in cells and mice with efficacy similar to current treatments, showing promise for fighting COVID-19.
www.nature.com/articles/s41...
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase - Nature
The development of a first-in-class non-covalent small-molecule inhibitor of SARS-CoV-2 replication that targets the viral guanine-N7 methyltransferase NSP14 is reported.
www.nature.com
December 12, 2024 at 2:25 PM
A new study from Rockefeller University developed TDI-015051, a potent antiviral targeting SARS-CoV-2’s NSP14 protein.
It inhibits viral replication in cells and mice with efficacy similar to current treatments, showing promise for fighting COVID-19.
www.nature.com/articles/s41...
It inhibits viral replication in cells and mice with efficacy similar to current treatments, showing promise for fighting COVID-19.
www.nature.com/articles/s41...
Identification and characterization of candidate inhibitors of the SARS-CoV-2 nsp14 3′-5′ exoribonuclease
www.microbiologyresearch.org/content/jour...
www.microbiologyresearch.org/content/jour...
Identification and characterization of candidate inhibitors of the SARS-CoV-2 nsp14 3′-5′ exoribonuclease
Coronaviruses such as SARS-CoV-2 possess the largest positive-sense RNA virus genomes (30 kb). This poses a fidelity problem as the inherent lack of proof-reading capacity of the viral RNA-dependent R...
www.microbiologyresearch.org
December 22, 2025 at 1:54 PM
Identification and characterization of candidate inhibitors of the SARS-CoV-2 nsp14 3′-5′ exoribonuclease
www.microbiologyresearch.org/content/jour...
www.microbiologyresearch.org/content/jour...
Loss of nsp14-exonuclease activity impairs the replication, proofreading, fitness and pathogenesis of SARS-CoV-2 https://www.biorxiv.org/content/10.64898/2026.01.12.698941v1
January 14, 2026 at 4:23 AM
Loss of nsp14-exonuclease activity impairs the replication, proofreading, fitness and pathogenesis of SARS-CoV-2 https://www.biorxiv.org/content/10.64898/2026.01.12.698941v1
Study reveals inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase by small molecules, key in COVID-19 treatment. #COVID19 #Biomed #DrugDiscovery PMID:39663451, Nature 2025, @Nature https://doi.org/10.1038/s41586-024-08320-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪
Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase | Nature
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. The rapid development of highly effective vaccines2,3 against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics4 have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity5. Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant (Kd) of 61 pM and a half-maximal effective con
doi.org
April 12, 2025 at 6:30 AM
Study reveals inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase by small molecules, key in COVID-19 treatment. #COVID19 #Biomed #DrugDiscovery PMID:39663451, Nature 2025, @Nature https://doi.org/10.1038/s41586-024-08320-0 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪