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.

An activator of G protein-coupled receptor and MEK1/2-ERK1/2 signaling inhibits HIV-1 replication by altering viral RNA processing

“…As a test of this approach, we examined small molecule modulators of SMN2 RNA AS and identified 5342191 as an inhibitor of HIV-1 replication. While targeting components of the core splicing apparatus (requiring coordinated functioning of many host proteins for removal of introns from RNAs) may be toxic [65], modulation of factors regulating splice site use, such as SR proteins or heterogeneous nuclear ribonucleoproteins, may not have as severe of an effect on the host [27,39,41,42,66]. Our characterization of 5342191 as a potent inhibitor of HIV-1 replication (Fig 1) validates this hypothesis.…”

“…Rev is critical in mediating nuclear export of incompletely-spliced (US/SS) HIV-1 RNAs to the cytoplasm while Tat is essential as a transactivator of viral transcription [35][36][37][38]. These results (and data on HIV-1 RNAs and SR proteins described below) are in mark contrast to previous HIV-1 RNA-processing inhibitors reported, suggesting a novel mechanism of action [27,28,33,[39][40][41][42][43].…”

The emerging role of alternative splicing in senescence and aging

“…Compounds targeting generic splicing factors, such as SF3B1, may find a use as anticancer agents. As compounds that control the activity of SR proteins are being identified (Shkreta et al ., ; Sigala et al ., ), their pro‐apoptotic or antisenescent activities will need to be investigated. Overall, while additional links between splicing and different facets of aging will continue to be uncovered, compounds that can modulate specific splicing events or relevant splicing programs may offer innovative approaches to correct or postpone age‐related disorders.…”

Benzothiazoles as potential antiviral agents

“…This compound was evaluated against the isolate (E00443), which greatly reduced susceptibility to NNRTI's and remained active, with an EC 50 of 1.3 µM ( Figure 11). [61] Protease inhibitors HIV-1 protease (HP) is essential for the life-cycle of HIV and the maturation of infective HIV virion by catalysing the hydrolysis of Gag and Gag-pol polyproteins resulting in the production of structural proteins, such as viral envelope glycoproteins and the enzymes reverse transcriptase, integrase, and protease. [62] Thus, it is an important target for HIV treatments.…”