ArticlePloS one2012
Small molecules targeted to a non-catalytic "RVxF" binding site of protein phosphatase-1 inhibit HIV-1.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 36 citations in OpenAlex.
- HIV-Tat and vascular endothelium: implications in the HIV associated brain, heart, and lung complications.Frontiers in immunology · 2025Review
- Emerging roles of the Protein Phosphatase 1 (PP1) in the context of viral infections.Cell communication and signaling : CCS · 2024Review
- Eukaryotic-like Phosphoprotein Phosphatase (PPP) enzyme evolution: interactions with environmental toxins and regulatory proteins.Bioscience reports · 2023Article
- HIV-1 Transcription Inhibitor 1E7-03 Decreases Nucleophosmin Phosphorylation.Molecular & cellular proteomics : MCP · 2023Article
- PP1, PP2A and PP2B Interplay in the Regulation of Sperm Motility: Lessons from Protein Phosphatase Inhibitors.International journal of molecular sciences · 2022Review
- The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma.International journal of molecular sciences · 2022Article
- Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple-negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta.Clinical and translational medicine · 2022Article
- Structural Optimization of 2,3-Dihydro-1H-cyclopenta[ACS infectious diseases · 2020Article
- A High-Throughput HIV-1 Drug Screening Platform, Based on Lentiviral Vectors and Compatible with Biosafety Level-1.Viruses · 2020Article
- Diversity of small molecule HIV-1 latency reversing agents identified in low- and high-throughput small molecule screens.Medicinal research reviews · 2020Review
- Targeting the Non-catalytic RVxF Site of Protein Phosphatase-1 With Small Molecules for Ebola Virus Inhibition.Frontiers in microbiology · 2019Article
- 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
- Article
- Protein Phosphatase-1 regulates Rift Valley fever virus replication.Antiviral research · 2016Article
- Reactivation of latent HIV-1 provirus via targeting protein phosphatase-1.Retrovirology · 2015Article
- Evolution of an epigenetic gene ensemble within the genus Anopheles.Genome biology and evolution · 2015Article
- 1E7-03, a low MW compound targeting host protein phosphatase-1, inhibits HIV-1 transcription.British journal of pharmacology · 2014Article
- Role of protein phosphatase 1 in dephosphorylation of Ebola virus VP30 protein and its targeting for the inhibition of viral transcription.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
HIV-1 Tat protein recruits host cell factors including CDK9/cyclin T1 to HIV-1 TAR RNA and thereby induces HIV-1 transcription. An interaction with host Ser/Thr protein phosphatase-1 (PP1) is critical for this function of Tat. PP1 binds to a Tat sequence, Q(35)VCF(38), which resembles the PP1-binding "RVxF" motif present on PP1-binding regulatory subunits. We showed that expression of PP1 binding peptide, a central domain of Nuclear Inhibitor of PP1, disrupted the interaction of HIV-1 Tat with PP1 and inhibited HIV-1 transcription and replication. Here, we report small molecule compounds that target the "RVxF"-binding cavity of PP1 to disrupt the interaction of PP1 with Tat and inhibit HIV-1 replication. Using the crystal structure of PP1, we virtually screened 300,000 compounds and identified 262 small molecules that were predicted to bind the "RVxF"-accommodating cavity of PP1. These compounds were then assayed for inhibition of HIV-1 transcription in CEM T cells. One of the compounds, 1H4, inhibited HIV-1 transcription and replication at non-cytotoxic concentrations. 1H4 prevented PP1-mediated dephosphorylation of a substrate peptide containing an RVxF sequence in vitro. 1H4 also disrupted the association of PP1 with Tat in cultured cells without having an effect on the interaction of PP1 with the cellular regulators, NIPP1 and PNUTS, or on the cellular proteome. Finally, 1H4 prevented the translocation of PP1 to the nucleus. Taken together, our study shows that HIV- inhibition can be achieved through using small molecules to target a non-catalytic site of PP1. This proof-of-principle study can serve as a starting point for the development of novel antiviral drugs that target the interface of HIV-1 viral proteins with their host partners.
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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.