ArticleBritish journal of pharmacology2014
1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription.
Article in British journal of pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 33 citations in OpenAlex.
- Article
- CK1 and PP1 regulate Rift Valley fever virus genome replication through L protein phosphorylation.Antiviral research · 2024Article
- Emerging roles of the Protein Phosphatase 1 (PP1) in the context of viral infections.Cell communication and signaling : CCS · 2024Review
- HIV-1 Transcription Inhibitor 1E7-03 Decreases Nucleophosmin Phosphorylation.Molecular & cellular proteomics : MCP · 2023Article
- Advances in the Development of Small Molecule Antivirals against Equine Encephalitic Viruses.Viruses · 2023Review
- PP1, PP2A and PP2B Interplay in the Regulation of Sperm Motility: Lessons from Protein Phosphatase Inhibitors.International journal of molecular sciences · 2022Review
- Deciphering the Role of Protein Phosphatases in Apicomplexa: The Future of Innovative Therapeutics?Microorganisms · 2022Review
- Restriction of HIV-1 infection in sickle cell trait.Blood advances · 2021Article
- Targeting Tat-TAR RNA Interaction for HIV-1 Inhibition.Viruses · 2021Article
- Protein Phosphatase 1 Regulates Human Cytomegalovirus Protein Translation by Restraining AMPK Signaling.Frontiers in microbiology · 2021Article
- Structural Optimization of 2,3-Dihydro-1H-cyclopenta[ACS infectious diseases · 2020Article
- Diversity of small molecule HIV-1 latency reversing agents identified in low- and high-throughput small molecule screens.Medicinal research reviews · 2020Review
- Article
- Article
- Targeting the Non-catalytic RVxF Site of Protein Phosphatase-1 With Small Molecules for Ebola Virus Inhibition.Frontiers in microbiology · 2019Article
- Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics.Biochimica et biophysica acta. Molecular cell research · 2019Review
- Protein Phosphatase 1-Targeting Small-Molecule C31 Inhibits Ebola Virus Replication.The Journal of infectious diseases · 2018Article
- Protein Phosphatase 1α Interacts with Venezuelan Equine Encephalitis Virus Capsid Protein and Regulates Viral Replication through Modulation of Capsid Phosphorylation.Journal of virology · 2018Article
- Inhibition of HIV-1 infection in humanized mice and metabolic stability of protein phosphatase-1-targeting small molecule 1E7-03.Oncotarget · 2017Article
- Protein Phosphatase-1 -targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals.Current pharmaceutical design · 2017Review
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
Abstract
background and purposeHIV-1 transcription is activated by the Tat protein which recruits the cyclin-dependent kinase CDK9/cyclin T1 to TAR RNA. Tat binds to protein phosphatase-1 (PP1) through the Q(35) VCF(38) sequence and translocates PP1 to the nucleus. PP1 dephosphorylates CDK9 and activates HIV-1 transcription. We have synthesized a low MW compound 1H4, that targets PP1 and prevents HIV-1 Tat interaction with PP1 and inhibits HIV-1 gene transcription. Here, we report our further work with the 1H4-derived compounds and analysis of their mechanism of action. EXPERIMENTAL APPROACH: Using the 1H4-PP1 complex as a model, we iteratively designed and synthesized follow-up libraries that were analysed for the inhibition of HIV-1 transcription and toxicity. We also confirmed the mechanism of action of the PP1-targeting molecules by determining the affinity of binding of these molecules to PP1, by analysing their effects on PP1 activity, disruption of PP1 binding to Tat and shuttling of PP1 to the nucleus. KEY
resultsWe identified a tetrahydroquinoline derivative, compound 7, which disrupted the interaction of Tat with PP1. We further optimized compound 7 and obtained compound 7c, renamed 1E7-03, which inhibited HIV-1 with low IC50 (fivefold lower than the previously reported compound, 1H4), showed no cytotoxicity and displayed a plasma half-life greater than 8 h in mice. 1E7-03 bound to PP1 in vitro and prevented shuttling of PP1 into the nucleus. CONCLUSIONS AND IMPLICATIONS: Our study shows that low MW compounds that functionally mimic the PP1-binding RVxF peptide can inhibit HIV-1 transcription by deregulating PP1.
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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.