4.6 Article

Small Molecules Targeted to a Non-Catalytic RVxF Binding Site of Protein Phosphatase-1 Inhibit HIV-1

期刊

PLOS ONE
卷 7, 期 6, 页码 -

出版社

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0039481

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资金

  1. Civilian Research and Development Foundation [UKB2-2927-KV-07]
  2. National Institutes of Health (NIH) [2 R25 HL003679-08]
  3. Office of Research on Minority Health [2MO1 RR10284, 1SC1GM082325-01, K25GM097501]
  4. Howard University
  5. RCMI-NIH from the Research Centers in Minority Institutions (RCMI) Program (Division of Research Infrastructure, National Center for Research Resources, NIH) [RCMI-NIH 2G12RR003048]
  6. National Heart, Lung, and Blood Institute

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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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