title: Modulation of the splicing regulatory function of SRSF10 by a novel compound that impairs HIV-1 replication.
abstract: 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 hTra2β, 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 hTra2β, 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.
authors.affiliation: Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
authors.forename: Lulzim
authors.initials: L
authors.lastname: Shkreta
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Blanchette
authors.affiliation: Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Toutant
authors.affiliation: Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Wilhelm
authors.affiliation: Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
authors.forename: Brendan
authors.initials: B
authors.lastname: Bell
authors.affiliation: Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Story
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: Ahalya
authors.initials: A
authors.lastname: Balachandran
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Cochrane
authors.affiliation: BC Centre for Excellence in HIV/AIDS, 608-1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Cheung
authors.affiliation: BC Centre for Excellence in HIV/AIDS, 608-1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.|Department of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Grierson
authors.affiliation: Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1E 4K8, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Chabot
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects*; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012322:RNA Precursors / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C000622059:1C8 compound; D019380:Anti-HIV Agents; D052160:Benzothiazoles; D018797:Cell Cycle Proteins; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D012097:Repressor Proteins; C115188:SRSF10 protein, human; D000068103:Serine-Arginine Splicing Factors; D009536:Niacinamide