ArticlePLoS pathogens2014
Discovery of a novel compound with anti-venezuelan equine encephalitis virus activity that targets the nonstructural protein 2.
Article in PLoS pathogens, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- The life cycle of the alphaviruses: From an antiviral perspective.Antiviral research · 2023Pooled it
- Discovery of a potent anti-Zika virus benzamide series targeting the viral protein NS4B.PLoS pathogens · 2026Article
- Discovery of a potent anti-Zika virus benzamide series targeting the viral protein NS4B.bioRxiv : the preprint server for biology · 2025Article
- Broad spectrum antiviral BDGR-164 provides protection against lethal neurotropic alphavirus infection in mice.Antiviral research · 2025Article
- The antiviral BDGR-49 provides protection from lethal, neurotropic Venezuelan equine encephalitis virus intranasal infection in mice.Journal of virology · 2025Article
- Alphavirus nsP2: A Multifunctional Regulator of Viral Replication and Promising Target for Anti-Alphavirus Therapies.Reviews in medical virology · 2025Review
- Identification of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A high-throughput response to the SARS-CoV-2 pandemic.SLAS discovery : advancing life sciences R & D · 2024Article
- Current challenges in the discovery of treatments against Mayaro fever.Expert opinion on therapeutic targets · 2024Review
- Neurological manifestations of encephalitic alphaviruses, traumatic brain injuries, and organophosphorus nerve agent exposure.Frontiers in neuroscience · 2024Review
- Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models.Science translational medicine · 2023Article
- Distinct Cellular Tropism and Immune Responses to Alphavirus Infection.Annual review of immunology · 2022Review
- Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors.Molecules (Basel, Switzerland) · 2021Article
- Identification of Quinolinones as Antivirals against Venezuelan Equine Encephalitis Virus.Antimicrobial agents and chemotherapy · 2021Article
- Emergence and Magnitude of ML336 Resistance in Venezuelan Equine Encephalitis Virus Depend on the Microenvironment.Journal of virology · 2020Article
- Benzamidine ML336 inhibits plus and minus strand RNA synthesis of Venezuelan equine encephalitis virus without affecting host RNA production.Antiviral research · 2020Article
- Application ofFrontiers in chemistry · 2020Review
- Efficacy of a ML336 derivative against Venezuelan and eastern equine encephalitis viruses.Antiviral research · 2019Article
- Telescoped synthesis of C3-functionalized (E)-arylamidines using Ugi-Mumm and regiospecific quinazolinone rearrangements.Organic & biomolecular chemistry · 2019Article
- Lipid-Coated Mesoporous Silica Nanoparticles for the Delivery of the ML336 Antiviral to Inhibit Encephalitic Alphavirus Infection.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
21 authors at 7 institutions in 1 country.
Funding
Abstract
Alphaviruses present serious health threats as emerging and re-emerging viruses. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, can cause encephalitis in humans and horses, but there are no therapeutics for treatment. To date, compounds reported as anti-VEEV or anti-alphavirus inhibitors have shown moderate activity. To discover new classes of anti-VEEV inhibitors with novel viral targets, we used a high-throughput screen based on the measurement of cell protection from live VEEV TC-83-induced cytopathic effect to screen a 340,000 compound library. Of those, we identified five novel anti-VEEV compounds and chose a quinazolinone compound, CID15997213 (IC50 = 0.84 µM), for further characterization. The antiviral effect of CID15997213 was alphavirus-specific, inhibiting VEEV and Western equine encephalitis virus, but not Eastern equine encephalitis virus. In vitro assays confirmed inhibition of viral RNA, protein, and progeny synthesis. No antiviral activity was detected against a select group of RNA viruses. We found mutations conferring the resistance to the compound in the N-terminal domain of nsP2 and confirmed the target residues using a reverse genetic approach. Time of addition studies showed that the compound inhibits the middle stage of replication when viral genome replication is most active. In mice, the compound showed complete protection from lethal VEEV disease at 50 mg/kg/day. Collectively, these results reveal a potent anti-VEEV compound that uniquely targets the viral nsP2 N-terminal domain. While the function of nsP2 has yet to be characterized, our studies suggest that the protein might play a critical role in viral replication, and further, may represent an innovative opportunity to develop therapeutic interventions for alphavirus infection.
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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.