Small molecules inhibitors of the heterogeneous ribonuclear protein A18 (hnRNP A18): a regulator of protein translation and an immune checkpoint

Solano-González, Eduardo; Coburn, Katherine M.; Yu, Wenbo; Wilson, Gerald M.; Nurmemmedov, Elmar; Kesari, Santosh; Chang, Elizabeth; MacKerell, Alexander D.; Weber, David J.

doi:10.1093/nar/gkaa1254

Cited by 12 publications

(19 citation statements)

References 42 publications

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“…Although there has been less research development into the identification of agents able to release HIV-1 splicing blocks, future studies should deepen into discovery and repurposing of agents that act on the host cell alternative splicing mechanisms employed by the virus during vRNA processing. For instance, HIV-1 splicing blocks can potentially be released by altering the function of hnRNP proteins that bind inhibitory exonic splicing silencers ( Carabet et al., 2019 ; Solano-Gonzalez et al., 2021 ) or inhibit surveillance mechanisms that promote vRNA degradation ( Durand et al., 2007 ; Popp and Maquat, 2015 ). Another possibility to enhance HIV-1 splicing is by modulating splicing site usage by small molecules or RNA interference therapeutics (see Section 5.3).…”

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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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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“…CIRBP has been extensively investigated for its ability to modulate cellular redox status by promoting the expression of antioxidant genes, such as TRX and CoQs, to quench ROS, thereby benefiting cell survival 8 , 29 , 30 . To our knowledge, ROS are reckoned as a culprit to arouse chemo-cardiotoxicity, resulting into crippled DNA repair system, disabled ATP synthesis, and cellular membrane damage 1 , 4 , 31 .…”

Section: Discussionmentioning

confidence: 99%

CIRBP-OGFR axis safeguards against cardiomyocyte apoptosis and cardiotoxicity induced by chemotherapy

Liu¹,

Cheng²,

Xing³

et al. 2022

Int. J. Biol. Sci.

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Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.

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“…RBPs are rapidly emerging as therapeutic targets ( 15–22 ). However, targeting RBPs with small molecules is still a challenge because most RBPs are considered undruggable due to a lack of well-defined binding pockets ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis

Tan

Sun

et al. 2022

Nucleic Acids Research

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CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-γ secretion and suppresses TGF-β1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-γ mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.

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Small molecules inhibitors of the heterogeneous ribonuclear protein A18 (hnRNP A18): a regulator of protein translation and an immune checkpoint

Cited by 12 publications

References 42 publications

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

CIRBP-OGFR axis safeguards against cardiomyocyte apoptosis and cardiotoxicity induced by chemotherapy

Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis

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