Evidence map›Paper›PMID 40910582›Full record

ArticleJournal of medicinal chemistry2025

Discovery, Optimization, and Evaluation of Non-Nucleoside SARS-CoV-2 NSP14 Inhibitors.

Michael W Miller, Cindy Meyer, Aitor Garzia, Hans-Heinrich Hoffmann, Tanweer A Khan, Melissa Egbertson, Robert W Myers, Nigel Liverton, Stacia Kargman, Jada A Davis and 9 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors.

Michael W MillerSanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Cindy MeyerLaboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.ORCID 0000-0003-3807-8383
Aitor GarziaLaboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Hans-Heinrich HoffmannLaboratory of Virology and Infectious Disease, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Tanweer A KhanSanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Melissa EgbertsonMelissa Egbertson Consulting LLC, 1232 Lois Road, Ambler, Pennsylvania 19002, United States.
Robert W MyersSanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.ORCID 0000-0003-2599-1050
Nigel LivertonSanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Stacia KargmanSanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Jada A DavisLaboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.ORCID 0009-0007-3256-8978
Oleg GanichkinPROTEROS Biostructures GmbH, Bunsenstrasse 7a, 82152 Planegg-Martinsried, Germany.
Julius NitschePROTEROS Biostructures GmbH, Bunsenstrasse 7a, 82152 Planegg-Martinsried, Germany.
Stefan SteinbacherPROTEROS Biostructures GmbH, Bunsenstrasse 7a, 82152 Planegg-Martinsried, Germany.
Shlomi DaganFisher Drug Discovery Resource Center, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
J Fraser GlickmanFisher Drug Discovery Resource Center, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Charles M RiceLaboratory of Virology and Infectious Disease, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Thomas TuschlLaboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Peter T MeinkeSanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.ORCID 0000-0002-7548-6215
David J HugginsSanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.ORCID 0000-0003-1579-2496

Funding

Virology CoreU19AI171401 · NIAID · HACKENSACK UNIVERSITY MEDICAL CENTER · PI PERLIN, DAVID S, RICE, CHARLES M · 2022 to 2022
$65.1M
NIAID NIH HHS U19 AI171401
6 · The paper itself

Abstract

We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity. Thermal shift assay data and available crystal structures led us to develop a model of the novel inhibitory ternary complex (NSP14, SAH, inhibitor), which was validated with a crystal structure of the complex. The advances described here enabled a successful proof-of-concept study that validated SARS-CoV-2 NSP14 as a novel drug target for COVID-19 and represent the first demonstration of pharmacological inhibition of viral methyltransferases as a viable avenue for an antiviral therapeutic.

Indexed as

Antiviral AgentsCOVID-19 Drug TreatmentDrug DiscoveryEnzyme InhibitorsMethyltransferasesSARS-CoV-2Viral Nonstructural ProteinsCOVID-19ExoribonucleasesHumansStructure-Activity RelationshipAntiviral AgentsEnzyme InhibitorsExoribonucleasesMethyltransferasesNSP14 protein, SARS-CoV-2Viral Nonstructural Proteins

Identifiers

PMID40910582
PMCPMC12425460

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.