ArticleJournal of virology2013
3C protease of enterovirus 68: structure-based design of Michael acceptor inhibitors and their broad-spectrum antiviral effects against picornaviruses.
Article in Journal of virology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed.
- Novel NSAID-Se derivative YSN-1-167 against Enterovirus 71 infection by inhibiting 3DAntimicrobial agents and chemotherapy · 2026Article
- Advances in Antiviral Drug Development Targeting Enteroviruses: From Viral Proteins to Host Factors.Viruses · 2026Review
- A clinical SARS-CoV-2 Mpro inhibitor blocks replication of multiple enteroviruses and confers oral in vivo protection in animal models.PLoS pathogens · 2026Article
- Structural insights into the antiviral efficacy of AG7404 against human rhinovirus 3C proteases.IUCrJ · 2026Article
- Epoxy tetrahydrophthalimides as potential bioactive agents: synthesis and computational study.Pest management science · 2025Article
- Structural basis for 3C and 3CD recruitment by enteroviral genomes during negative-strand RNA synthesis.Nature communications · 2025Article
- Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease.Journal of medicinal chemistry · 2025Article
- Article
- Emerging Therapeutics in the Fight Against EV-D68: A Review of Current Strategies.Influenza and other respiratory viruses · 2024Review
- A Structural Investigation of the Interaction between a GC-376-Based Peptidomimetic PROTAC and Its Precursor with the Viral Main Protease of Coxsackievirus B3.Biomolecules · 2024Article
- Elucidating the Substrate Envelope of Enterovirus 68-3C Protease: Structural Basis of Specificity and Potential Resistance.Viruses · 2024Article
- Crystal structures of the 3C proteases from Coxsackievirus B3 and B4.Acta crystallographica. Section F, Structural biology communications · 2024Article
- Potent small molecule inhibitors against the 3C protease of foot-and-mouth disease virus.Microbiology spectrum · 2024Article
- Preclinical evaluation of the SARS-CoV-2 MNature microbiology · 2024Article
- An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations.Science translational medicine · 2024Article
- Advances in anti-EV-A71 drug development research.Journal of advanced research · 2024Review
- Structure-Based Lead Optimization of Enterovirus D68 2A Protease Inhibitors.Journal of medicinal chemistry · 2023Article
- Pharmacophore Oriented MP2 Characterization of Charge Distribution for Anti-SARS-CoV-2 Inhibitor Nirmatrelvir.Journal of molecular structure · 2023Article
- Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.Journal of medicinal chemistry · 2023Article
- Advancement of Computational Design Drug Delivery System in COVID-19: Current Updates and Future Crosstalk- A Critical update.Infectious disorders drug targets · 2023Article
14 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We have determined the cleavage specificity and the crystal structure of the 3C protease of enterovirus 68 (EV68 3C(pro)). The protease exhibits a typical chymotrypsin fold with a Cys...His...Glu catalytic triad; its three-dimensional structure is closely related to that of the 3C(pro) of rhinovirus 2, as well as to that of poliovirus. The phylogenetic position of the EV68 3C(pro) between the corresponding enzymes of rhinoviruses on the one hand and classical enteroviruses on the other prompted us to use the crystal structure for the design of irreversible inhibitors, with the goal of discovering broad-spectrum antiviral compounds. We synthesized a series of peptidic α,β-unsaturated ethyl esters of increasing length and for each inhibitor candidate, we determined a crystal structure of its complex with the EV68 3C(pro), which served as the basis for the next design round. To exhibit inhibitory activity, compounds must span at least P3 to P1'; the most potent inhibitors comprise P4 to P1'. Inhibitory activities were found against the purified 3C protease of EV68, as well as with replicons for poliovirus and EV71 (50% effective concentration [EC(50)] = 0.5 μM for the best compound). Antiviral activities were determined using cell cultures infected with EV71, poliovirus, echovirus 11, and various rhinovirus serotypes. The most potent inhibitor, SG85, exhibited activity with EC(50)s of ≈180 nM against EV71 and ≈60 nM against human rhinovirus 14 in a live virus-cell-based assay. Even the shorter SG75, spanning only P3 to P1', displayed significant activity (EC(50) = 2 to 5 μM) against various rhinoviruses.
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