The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation

Dahal, Subha; Cheng, Ran; Cheung, Peter K.; Been, Terek; Malty, Ramy H.; Geng, Melissa; Manianis, Sarah; Shkreta, Lulzim; Jahanshahi, Shahrazad; Toutant, Johanne; Chan, Rose; Park, Sean S.; Brockman, Mark A.; Babu, Mohan; Mubareka, Samira; Mossman, Karen; Banerjee, Arinjay; Gray-Owen, Scott D.; Brown, Martha; Houry, Walid; Chabot, Benoit; Grierson, David S.; Cochrane, Alan

doi:10.3390/v14010060

Cited by 13 publications

(13 citation statements)

References 110 publications

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“…Several studies have focused on modulating cellular splicing factors such as SR and hnRNP proteins to alter HIV-1 gene expression [23,81,82]. The identification of multiple small molecules (digoxin, ABX464, didehydro-cortistatin A, 8-azaguanine, 5310150, 1C8, 791, 191, filgotinib, GPS491) that inhibit HIV-1 gene expression post-integration by modulating viral RNA processing with limited impact on host cell viability demonstrates the feasibility of this approach [35,37,[40][41][42][43][83][84][85].…”

Section: Discussionmentioning

confidence: 99%

Opposing roles of CLK SR kinases in controlling HIV-1 gene expression and latency

et al. 2022

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Background The generation of over 69 spliced HIV-1 mRNAs from one primary transcript by alternative RNA splicing emphasizes the central role that RNA processing plays in HIV-1 replication. Control is mediated in part through the action of host SR proteins whose activity is regulated by multiple SR kinases (CLK1-4, SRPKs). Methods Both shRNA depletion and small molecule inhibitors of host SR kinases were used in T cell lines and primary cells to evaluate the role of these factors in the regulation of HIV-1 gene expression. Effects on virus expression were assessed using western blotting, RT-qPCR, and immunofluorescence. Results The studies demonstrate that SR kinases play distinct roles; depletion of CLK1 enhanced HIV-1 gene expression, reduction of CLK2 or SRPK1 suppressed it, whereas CLK3 depletion had a modest impact. The opposing effects of CLK1 vs. CLK2 depletion were due to action at distinct steps; reduction of CLK1 increased HIV-1 promoter activity while depletion of CLK2 affected steps after transcript initiation. Reduced CLK1 expression also enhanced the response to several latency reversing agents, in part, by increasing the frequency of responding cells, consistent with a role in regulating provirus latency. To determine whether small molecule modulation of SR kinase function could be used to control HIV-1 replication, we screened a GSK library of protein kinase inhibitors (PKIS) and identified several pyrazolo[1,5-b] pyridazine derivatives that suppress HIV-1 gene expression/replication with an EC50 ~ 50 nM. The compounds suppressed HIV-1 protein and viral RNA accumulation with minimal impact on cell viability, inhibiting CLK1 and CLK2 but not CLK3 function, thereby selectively altering the abundance of individual CLK and SR proteins in cells. Conclusions These findings demonstrate the unique roles played by individual SR kinases in regulating HIV-1 gene expression, validating the targeting of these functions to either enhance latency reversal, essential for “Kick-and-Kill” strategies, or to silence HIV protein expression for “Block-and-Lock” strategies.

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Section: Discussionmentioning

confidence: 99%

Opposing roles of CLK SR kinases in controlling HIV-1 gene expression and latency

et al. 2022

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“…The authors hypothesize that ABX464 could be able to induce aberrant HIV-1 transcripts that can be recognized by the immune system, leading to selective killing of infected cells ( Moron-Lopez et al., 2021 ). More recently, an anti-HIV-1 stilbene quinolone (GPS491) has been shown to modulate the abundance and function of host SR proteins, hence altering the HIV-1 splicing pattern and inhibiting the HIV-1 life cycle ( Dahal et al., 2022 ). Lastly, the design of drug screens coupled with transcriptomic analysis can broaden the range of HIV-1 splicing targeting compounds by multiple other mechanisms.…”

Section: Therapeutic Targeting Of Hiv-1 Rna Metabolism Pathwaysmentioning

confidence: 99%

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

Crespo

Rao

Mahmoudi

2022

Front. Cell. Infect. Microbiol.

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HIV-1 infection remains non-curative due to the latent reservoir, primarily a small pool of resting memory CD4+ T cells bearing replication-competent provirus. Pharmacological reversal of HIV-1 latency followed by intrinsic or extrinsic cell killing has been proposed as a promising strategy to target and eliminate HIV-1 viral reservoirs. Latency reversing agents have been extensively studied for their role in reactivating HIV-1 transcription in vivo, although no permanent reduction of the viral reservoir has been observed thus far. This is partly due to the complex nature of latency, which involves strict intrinsic regulation at multiple levels at transcription and RNA processing. Still, the molecular mechanisms that control HIV-1 latency establishment and maintenance have been almost exclusively studied in the context of chromatin remodeling, transcription initiation and elongation and most known LRAs target LTR-driven transcription by manipulating these. RNA metabolism is a largely understudies but critical mechanistic step in HIV-1 gene expression and latency. In this review we provide an update on current knowledge on the role of RNA processing mechanisms in viral gene expression and latency and speculate on the possible manipulation of these pathways as a therapeutic target for future cure studies.

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“…GPS491 ‡ GPS491 decreases the levels of unspliced and single-spliced viral RNAs, as well as the accumulation of three essential viral proteins. [89] Influenza virus PPMO PPMO promotes TMPRSS2-exon5 skipping to increase the expression of inactive TMPRSS2 form and thus suppress viral infectivity.…”

Section: Viral Infectionmentioning

confidence: 99%

Roles of alternative splicing in infectious diseases: from hosts, pathogens to their interactions

Lyu

Lai

Wang

et al. 2023

Chinese Medical Journal

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Alternative splicing (AS) is an evolutionarily conserved mechanism that removes introns and ligates exons to generate mature messenger RNAs (mRNAs), extremely improving the richness of transcriptome and proteome. Both mammal hosts and pathogens require AS to maintain their life activities, and inherent physiological heterogeneity between mammals and pathogens makes them adopt different ways to perform AS. Mammals and fungi conduct a two-step transesterification reaction by spliceosomes to splice each individual mRNA (named cis-splicing). Parasites also use spliceosomes to splice, but this splicing can occur among different mRNAs (named trans-splicing). Bacteria and viruses directly hijack the host's splicing machinery to accomplish this process. Infection-related changes are reflected in the spliceosome behaviors and the characteristics of various splicing regulators (abundance, modification, distribution, movement speed, and conformation), which further radiate to alterations in the global splicing profiles. Genes with splicing changes are enriched in immune-, growth-, or metabolism-related pathways, highlighting approaches through which hosts crosstalk with pathogens. Based on these infection-specific regulators or AS events, several targeted agents have been developed to fight against pathogens. Here, we summarized recent findings in the field of infection-related splicing, including splicing mechanisms of pathogens and hosts, splicing regulation and aberrant AS events, as well as emerging targeted drugs. We aimed to systemically decode host–pathogen interactions from a perspective of splicing. We further discussed the current strategies of drug development, detection methods, analysis algorithms, and database construction, facilitating the annotation of infection-related splicing and the integration of AS with disease phenotype.

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The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation

Cited by 13 publications

References 110 publications

Opposing roles of CLK SR kinases in controlling HIV-1 gene expression and latency

Opposing roles of CLK SR kinases in controlling HIV-1 gene expression and latency

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

Roles of alternative splicing in infectious diseases: from hosts, pathogens to their interactions

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