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De-repressing LncRNA-Targeted Genes to Upregulate Gene Expression: Focus on Small Molecule Therapeutics.

ABSTRACT: Non-protein coding RNAs (ncRNAs) make up the overwhelming majority of transcripts in the genome and have recently gained attention for their complex regulatory role in cells, including the regulation of protein-coding genes. Furthermore, ncRNAs play an important role in normal development and their expression levels are dysregulated in several diseases. Recently, several long noncoding RNAs (lncRNAs) have been shown to alter the epigenetic status of genomic loci and suppress the expression of target genes. This review will present examples of such a mechanism and focus on the potential to target lncRNAs for achieving therapeutic gene upregulation by de-repressing genes that are epigenetically silenced in various diseases. Finally, the potential to target lncRNAs, through their interactions with epigenetic enzymes, using various tools, such as small molecules, viral vectors and antisense oligonucleotides, will be discussed. We suggest that small molecule modulators of a novel class of drug targets, lncRNA-protein interactions, have great potential to treat some cancers, cardiovascular disease, and neurological disorders.

SUBMITTER: Fatemi RP

PROVIDER: S-EPMC4461991 | biostudies-other | 2014 Nov

REPOSITORIES: biostudies-other

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Project description:Antiviral compounds displaying several remarkable features have been identified by a uniquely enabling drug screen and advanced through validation in two animal models, and in human primary bronchial epithelial cells grown to an air-liquid interface (ALI) and infected with SARS-CoV-2 (Brazil). Activity is observed in the nanomolar range in mammalian cells in vitro against the six viral families causing most human respiratory viral disease, irrespective of strain, including SARS-CoV-2 delta variant. A substantial barrier to development of viral resistance is demonstrated for influenza (FLUV). The drug target is an allosteric site on a novel host multi-protein complex (MPC) formed transiently, in an energy-dependent fashion, and composed of proteins implicated in viral lifecycles and innate immunity. The composition of this host MPC is modified in viral family-specific ways by FLUV and CoV, and substantially restored to the uninfected state with drug treatment. SQSTM1/p62, a key regulator of the autophagy pathway of innate immunity is i) found in the target MPC from uninfected cells, ii) lost upon infection, and iii) restored by drug treatment of infected cells, as assessed by drug resin affinity chromatography. A small subset of 14-3-3 is identified as the host protein to which the drug is bound. Advanced compounds with good oral bioavailability, half-life, lung exposure, and safety are approaching criteria for a Target Product Profile. We propose these novel drug targets to comprise a previously unappreciated molecular basis for homeostasis that is modified by viruses to facilitate their propagation and is restored by treatment with the therapeutic compounds presented. This discovery has transformative implications for treating respiratory viral-related disease, applicable to everything from COVID-19, seasonal influenza, common 'winter viruses' (respiratory syncytial virus, parainfluenza virus, rhinovirus, etc.), emerging respiratory viruses, and prevention of virus-induced asthma/COPD exacerbations. Treating respiratory viral disease with these host-targeted pan-respiratory viral family active compounds early, upon onset of symptoms of viral upper respiratory infection, irrespective of cause, should protect against progression to lower respiratory tract or systemic infection, the hallmarks of serious illness.

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De-repressing LncRNA-Targeted Genes to Upregulate Gene Expression: Focus on Small Molecule Therapeutics.

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