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Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication.
Shkreta, Lulzim; Blanchette, Marco; Toutant, Johanne; Wilhelm, Emmanuelle; Bell, Brendan; Story, Benjamin A; Balachandran, Ahalya; Cochrane, Alan; Cheung, Peter K; Harrigan, P Richard; Grierson, David S; Chabot, Benoit.
Afiliação
  • Shkreta L; Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
  • Blanchette M; Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
  • Toutant J; Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
  • Wilhelm E; Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
  • Bell B; Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
  • Story BA; Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
  • Balachandran A; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • Cochrane A; Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • Cheung PK; BC Centre for Excellence in HIV/AIDS, 608-1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
  • Harrigan PR; BC Centre for Excellence in HIV/AIDS, 608-1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
  • Grierson DS; Department of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
  • Chabot B; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Nucleic Acids Res ; 45(7): 4051-4067, 2017 04 20.
Article em En | MEDLINE | ID: mdl-27928057
We recently identified the 4-pyridinone-benzisothiazole carboxamide compound 1C8 as displaying strong anti-HIV-1 potency against a variety of clinical strains in vitro. Here we show that 1C8 decreases the expression of HIV-1 and alters splicing events involved in the production of HIV-1 mRNAs. Although 1C8 was designed to be a structural mimic of the fused tetracyclic indole compound IDC16 that targets SRSF1, it did not affect the splice site shifting activity of SRSF1. Instead, 1C8 altered splicing regulation mediated by SRSF10. Depleting SRSF10 by RNA interference affected viral splicing and, like 1C8, decreased expression of Tat, Gag and Env. Incubating cells with 1C8 promoted the dephosphorylation of SRSF10 and increased its interaction with hTra2ß, a protein previously implicated in the control of HIV-1 RNA splicing. While 1C8 affects the alternative splicing of cellular transcripts controlled by SRSF10 and hTra2ß, concentrations greater than those needed to inhibit HIV-1 replication were required to elicit significant alterations. Thus, the ability of 1C8 to alter the SRSF10-dependent splicing of HIV-1 transcripts, with minor effects on cellular splicing, supports the view that SRSF10 may be used as a target for the development of new anti-viral agents.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Repressoras / Replicação Viral / HIV-1 / Processamento Alternativo / Niacinamida / Proteínas de Ciclo Celular / Fármacos Anti-HIV / Benzotiazóis / Fatores de Processamento de Serina-Arginina Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Repressoras / Replicação Viral / HIV-1 / Processamento Alternativo / Niacinamida / Proteínas de Ciclo Celular / Fármacos Anti-HIV / Benzotiazóis / Fatores de Processamento de Serina-Arginina Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article