ArticleProceedings of the National Academy of Sciences of the United States of America2008
A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 297 papers.
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.
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.
Who cites it
297 citing papers in PubMed, 527 citations in OpenAlex.
- Substrate-Selective Inhibition of the SARS-CoV-2 Papain-Like Protease: Inhibition of Hydrolysis of Human Over Viral Substrates.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- Target-Based Antiviral Drug Development Against Human Respiratory Viruses.Pathogens (Basel, Switzerland) · 2026Review
- Recent Advances in the Design of Inhibitors Targeting the Viral Entry and Replication of the SARS-CoV-2 Virus, Driven by In Silico Approaches.Molecules (Basel, Switzerland) · 2026Review
- Discovery of novel druggable binding pockets on SARS-CoV-2 PLpro via fragment screening and insights for structure-based inhibitor design.The Journal of biological chemistry · 2026Article
- The role of ubiquitin system in ageing-related diseases and potential therapeutic opportunities.Molecular biomedicine · 2026Review
- Targeting SARS-CoV-2 Non-Structural Proteins: A Blueprint for Next-Generation Small-Molecule Coronavirus Antivirals.Pharmaceutics · 2026Review
- Inhibitors Targeting SARS-CoV-2 Papain-Like Protease: Screening, Design, Synthesis, and Biological Evaluation.ChemMedChem · 2026Article
- Discovery of the SARS-CoV-2 Papain-Like Protease Inhibitor MR1-114: From Structure-Based Design toJournal of medicinal chemistry · 2026Article
- Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease.Journal of medicinal chemistry · 2026Article
- Mechanistic insights into the noncovalent inhibition of SARS-CoV-2 PLpro: a multiscale computational study.Journal of computer-aided molecular design · 2026Article
- Quinazolinone based broad-spectrum antiviral molecules: design, synthesis, in silico studies and biological evaluation.Molecular diversity · 2026Article
- YL1004 is a SARS-CoV-2 papain-like protease inhibitor with immunomodulatory and antiviral activity in mice.Nature communications · 2026Article
- Discovery of Fragment-Based Inhibitors of SARS-CoV-2 PLJournal of medicinal chemistry · 2026Article
- Discovery of SARS-CoV-2 PLpro inhibitors and RIPK1 inhibitors with synergistic antiviral efficacy in a mouse COVID-19 model.Acta pharmaceutica Sinica. B · 2026Article
- Chasing allosteric inhibition of the SARS-CoV-2 PLpro via molecular dynamics simulations with flooding fragments (MDFFr).Journal of computer-aided molecular design · 2025Article
- SARS-CoV‑2 Papain-Like Protease Inhibitors Based on Naphthalen-1-ylethanamine and Halogenated Benzene Moieties.ACS omega · 2025Article
- NMR screening of low molecular weight inhibitors targeting the papain-like protease (PLPro) of SARS-CoV-2.FEBS open bio · 2025Article
- 1,2,4-Thiadiazolidin-3,5-Diones as Inhibitors of Cysteine Proteases.Molecules (Basel, Switzerland) · 2025Article
- Screening of Medicines for Malaria Venture Open Boxes Identifies Potent SARS-CoV‑2 Papain-like Protease (PLACS omega · 2025Article
- Divergent resistance pathways amongst SARS-CoV-2 PLpro inhibitors highlight the need for scaffold diversity.PLoS pathogens · 2025Article
237 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
We report the discovery and optimization of a potent inhibitor against the papain-like protease (PLpro) from the coronavirus that causes severe acute respiratory syndrome (SARS-CoV). This unique protease is not only responsible for processing the viral polyprotein into its functional units but is also capable of cleaving ubiquitin and ISG15 conjugates and plays a significant role in helping SARS-CoV evade the human immune system. We screened a structurally diverse library of 50,080 compounds for inhibitors of PLpro and discovered a noncovalent lead inhibitor with an IC(50) value of 20 microM, which was improved to 600 nM via synthetic optimization. The resulting compound, GRL0617, inhibited SARS-CoV viral replication in Vero E6 cells with an EC(50) of 15 microM and had no associated cytotoxicity. The X-ray structure of PLpro in complex with GRL0617 indicates that the compound has a unique mode of inhibition whereby it binds within the S4-S3 subsites of the enzyme and induces a loop closure that shuts down catalysis at the active site. These findings provide proof-of-principle that PLpro is a viable target for development of antivirals directed against SARS-CoV, and that potent noncovalent cysteine protease inhibitors can be developed with specificity directed toward pathogenic deubiquitinating enzymes without inhibiting host DUBs.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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 OpenQuestion graph.