RNAs hold a lot of potential when it comes to druggable molecular targets

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Small Molecules ◽  
Drug Targets ◽  
Gene Sequencing ◽  
Molecular Targets ◽  
Effective Strategies ◽  
The Past ◽  
Promising Strategy ◽  
Non Coding Rna ◽  
Human Genes ◽  
Non Coding Rnas

Small molecules drugged just about 700 molecular targets. Most of these molecular targets are proteins, representing 0.5% of the proteome and 0.05% of the genome. It has also been proven that whereas 90% of human genes are transcribed into RNAs, only 2% are translated into proteins. Non-coding RNAs are transcribed from around 70% of human genes. As a result, RNAs hold a lot of potential when it comes to druggable molecular targets, yet they've long been regarded as intractable.MiRNAs are a sort of non-coding RNA that finely regulates gene expression in human cells and has been connected to the development of diseases such as cancer. Using small compounds to drug miRNAs is a distinct and promising strategy, while miRNAs have long been recognized as drug targets and ASOs that block miRNAs have been used in clinical studies. In the past, small drugs targeting alternative biomolecules to indirectly influence miRNAs have been found, but small compounds directly targeting miRNAs offer more potential as therapeutic possibilities. This review summarized recently found chemicals that might directly target miRNAs. When these small molecules connect to miRNAs, they either block or degrade miRNA. These small molecules have also been shown to be beneficial in cancer therapy.In the future, several challenges must be solved to boost the potency of small molecules in drug miRNAs. For starters, discovering a strongly specific miRNA SMI is crucial for medicinal development. While the strategies previously released have shown promise in discovering SMIs, new effective strategies must be created or existing approaches must be enhanced. Second, biotechnologies like gene sequencing and pull-down methods should be combined to test and boost the specificity of identified SMIs. Third, new small-molecule functionalities that can more efficiently degrade RNAs are needed to generate SMDs that work as miRNA degraders. Fourth, most SMIs and SMDs' on-target and off-target toxicity was not adequately examined. This requires detailed bio-safety analyses of manufactured SMIs and SMDs.Finally, a brief summary of small drugs that can directly target miRNAs. MiRNA inhibition and cancer therapy revealed both the efficacy and selectivity of these small molecules. Hopefully, these and other future small molecules will open the door for therapy development that targets druggable miRNAs.

The role of non-coding RNA/microRNAs in cardiac disease

2018 ◽  
Author(s):  
Yolan J. Reckman ◽  
Yigal M. Pinto
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Hypertrophy ◽  
Cardiac Disease ◽  
Cardiac Development ◽  
Rna Transcripts ◽  
The Past ◽  
Non Coding Rna ◽  
Organ Systems ◽  
Non Coding Rnas

In the past two decades, our knowledge about non-coding DNA has increased tremendously. While non-coding DNA was initially discarded as ‘junk DNA’, we are now aware of the important and often crucial roles of RNA transcripts that do not translate into protein. Non-coding RNAs (ncRNAs) play important functions in normal cellular homeostasis and also in many diseases across all organ systems. Among the different ncRNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been studied the most. In this chapter we discuss the role of miRNAs and lncRNAs in cardiac disease. We present examples of miRNAs with fundamental roles in cardiac development (miR-1), hypertrophy (myomiRs, miR-199, miR-1/133), fibrosis (miR-29, miR-21), myocardial infarction (miR-15, miR17~92), and arrhythmias/conduction (miR-1). We provide examples of lncRNAs related to cardiac hypertrophy (MHRT, CHRF), myocardial infarction (ANRIL, MIAT), and arrhythmias (KCNQ1OT1). We also discuss miRNAs and lncRNAs as potential therapeutic targets or biomarkers in cardiac disease.

scholarly journals Pan-cancer systematic identification of lncRNAs associated with cancer prognosis

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8797 ◽  
Author(s):  
Matthew Ung ◽  
Evelien Schaafsma ◽  
Daniel Mattox ◽  
George L. Wang ◽  
Chao Cheng
Keyword(s):  
Drug Targets ◽  
Patient Survival ◽  
Cancer Prognosis ◽  
Rna Seq ◽  
Non Coding Rna ◽  
Cancer Types ◽  
Non Coding Rnas ◽  
Microarray Studies ◽  
Systematic Identification ◽  
Pan Cancer

Background The “dark matter” of the genome harbors several non-coding RNA species including Long non-coding RNAs (lncRNAs), which have been implicated in neoplasia but remain understudied. RNA-seq has provided deep insights into the nature of lncRNAs in cancer but current RNA-seq data are rarely accompanied by longitudinal patient survival information. In contrast, a plethora of microarray studies have collected these clinical metadata that can be leveraged to identify novel associations between gene expression and clinical phenotypes. Methods In this study, we developed an analysis framework that computationally integrates RNA-seq and microarray data to systematically screen 9,463 lncRNAs for association with mortality risk across 20 cancer types. Results In total, we identified a comprehensive list of associations between lncRNAs and patient survival and demonstrate that these prognostic lncRNAs are under selective pressure and may be functional. Our results provide valuable insights that facilitate further exploration of lncRNAs and their potential as cancer biomarkers and drug targets.

scholarly journals Long Non-Coding RNA in the Pathogenesis of Cancers

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1015 ◽  
Author(s):  
Chi ◽  
Wang ◽  
Wang ◽  
Yu ◽  
Yang
Keyword(s):  
Early Stage ◽  
Gene Expressions ◽  
Rna Transcripts ◽  
The Past ◽  
Non Coding Rna ◽  
Incidence And Mortality ◽  
Non Coding Rnas ◽  
Tumor Growth And Metastasis ◽  
New Biomarkers ◽  
Long Non Coding Rna

The incidence and mortality rate of cancer has been quickly increasing in the past decades. At present, cancer has become the leading cause of death worldwide. Most of the cancers cannot be effectively diagnosed at the early stage. Although there are multiple therapeutic treatments, including surgery, radiotherapy, chemotherapy, and targeted drugs, their effectiveness is still limited. The overall survival rate of malignant cancers is still low. It is necessary to further study the mechanisms for malignant cancers, and explore new biomarkers and targets that are more sensitive and effective for early diagnosis, treatment, and prognosis of cancers than traditional biomarkers and methods. Long non-coding RNAs (lncRNAs) are a class of RNA transcripts with a length greater than 200 nucleotides. Generally, lncRNAs are not capable of encoding proteins or peptides. LncRNAs exert diverse biological functions by regulating gene expressions and functions at transcriptional, translational, and post-translational levels. In the past decade, it has been demonstrated that the dysregulated lncRNA profile is widely involved in the pathogenesis of many diseases, including cancer, metabolic disorders, and cardiovascular diseases. In particular, lncRNAs have been revealed to play an important role in tumor growth and metastasis. Many lncRNAs have been shown to be potential biomarkers and targets for the diagnosis and treatment of cancers. This review aims to briefly discuss the latest findings regarding the roles and mechanisms of some important lncRNAs in the pathogenesis of certain malignant cancers, including lung, breast, liver, and colorectal cancers, as well as hematological malignancies and neuroblastoma.

scholarly journals New Approaches to Difficult Drug Targets: The Phosphatase Story

2017 ◽  
Vol 22 (9) ◽  
pp. 1071-1083 ◽  
Author(s):  
John S. Lazo ◽  
Kelley E. McQueeney ◽  
Elizabeth R. Sharlow
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Tyrosine Phosphatase ◽  
Drug Targets ◽  
Tyrosine Phosphatase ◽  
Molecular Targets ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Further Development ◽  
Enzyme Class

The drug discovery landscape is littered with promising therapeutic targets that have been abandoned because of insufficient validation, historical screening failures, and inferior chemotypes. Molecular targets once labeled as “undruggable” or “intractable” are now being more carefully interrogated, and while they remain challenging, many target classes are appearing more approachable. Protein tyrosine phosphatases represent an excellent example of a category of molecular targets that have emerged as druggable, with several small molecules and antibodies recently becoming available for further development. In this review, we examine some of the diseases that are associated with protein tyrosine phosphatase dysfunction and use some prototype contemporary strategies to illustrate approaches that are being used to identify small molecules targeting this enzyme class.

scholarly journals A survey of cis regulatory non-coding RNA involved in bacterial virulence

2021 ◽  
Author(s):  
Mohammad Reza Naghdi ◽  
Samia Djerroud ◽  
Katia Smail ◽  
Jonathan Perreault
Keyword(s):  
Drug Targets ◽  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Virulence Genes ◽  
Regulatory Elements ◽  
Non Coding Rna ◽  
Immune System Regulation ◽  
Non Coding Rnas ◽  
Physical And Chemical

Study of pathogenesis in bacteria is important to find new drug targets to treat bacterial infections. Pathogenic bacteria, including opportunists, express numerous so-called virulence genes to escape the host natural defenses and immune system. Regulation of virulence genes is often required for bacteria to infect their host. Such regulation can be achieved by cis-regulatory RNAs, like the metabolite-binding riboswitches or thermoregulators. In spite of the hundreds of RNA families annotated as cis-regulatory, there are relatively few examples of non-coding RNAs (ncRNAs) in 5′-UnTranslated Regions (UTRs) of bacteria described to regulate downstream virulence genes. To reassess the potential roles of such regulatory elements in bacterial pathogenesis, we collected genes important for virulence from different databases and evaluated the presence of ncRNAs in their UTRs to highlight the potential role of this type of gene regulation for virulence and, at the same time, get insight on some of the physical and chemical triggers of virulence.

scholarly journals Non-Coding RNA-Driven Regulation of rRNA Biogenesis

2020 ◽  
Vol 21 (24) ◽  
pp. 9738
Author(s):  
Eleni G. Kaliatsi ◽  
Nikoleta Giarimoglou ◽  
Constantinos Stathopoulos ◽  
Vassiliki Stamatopoulou
Keyword(s):  
Cell Viability ◽  
Ribosomal Rna ◽  
Genetic Information ◽  
Associated Factors ◽  
Molecular Targets ◽  
Concerted Action ◽  
Eukaryotic Nucleus ◽  
Non Coding Rna ◽  
Synthesis And Processing ◽  
Non Coding Rnas

Ribosomal RNA (rRNA) biogenesis takes place in the nucleolus, the most prominent condensate of the eukaryotic nucleus. The proper assembly and integrity of the nucleolus reflects the accurate synthesis and processing of rRNAs which in turn, as major components of ribosomes, ensure the uninterrupted flow of the genetic information during translation. Therefore, the abundant production of rRNAs in a precisely functional nucleolus is of outmost importance for the cell viability and requires the concerted action of essential enzymes, associated factors and epigenetic marks. The coordination and regulation of such an elaborate process depends on not only protein factors, but also on numerous regulatory non-coding RNAs (ncRNAs). Herein, we focus on RNA-mediated mechanisms that control the synthesis, processing and modification of rRNAs in mammals. We highlight the significance of regulatory ncRNAs in rRNA biogenesis and the maintenance of the nucleolar morphology, as well as their role in human diseases and as novel druggable molecular targets.

scholarly journals Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 403
Author(s):  
Luiz F. S. Oliveira ◽  
Danilo Predes ◽  
Helena L. Borges ◽  
Jose G. Abreu
Keyword(s):  
Colorectal Cancer ◽  
Small Molecules ◽  
Tumor Tissue ◽  
Patient Survival ◽  
Therapeutic Potential ◽  
Antitumor Activities ◽  
The Past ◽  
Naturally Occurring ◽  
Promising Strategy ◽  
Antitumor Properties

Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/β-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/β-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/β-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.

scholarly journals LncRNA analyses reveal increased levels of non-coding centromeric transcripts in hepatocellular carcinoma

2021 ◽  
Author(s):  
Anamaria Necsulea ◽  
Philippe Veber ◽  
Tuyana Boldanova ◽  
Charlotte KY Ng ◽  
Stefan Wieland ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressors ◽  
Drug Targets ◽  
Expression Patterns ◽  
Rna Seq ◽  
Adjacent Tissue ◽  
Satellite Repeats ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
New Biomarkers

The search for new biomarkers and drug targets for hepatocellular carcinoma (HCC) has spurred an interest in long non-coding RNAs (lncRNAs), often proposed as oncogenes or tumor suppressors. Furthermore, lncRNA expression patterns can bring insights into the global de-regulation of cellular machineries in tumors. Here, we examine lncRNAs in a large HCC cohort, comprising RNA-seq data from paired tumor and adjacent tissue biopsies from 114 patients. We find that numerous lncRNAs are differentially expressed between tumors and adjacent tissues and between tumor progression stages. Although we find strong differential expression for most lncRNAs previously associated with HCC, the expression patterns of several prominent HCC-associated lncRNAs disagree with their previously proposed roles. We examine the genomic characteristics of HCC-expressed lncRNAs and reveal an enrichment for repetitive elements among the lncRNAs with the strongest expression increases in advanced-stage tumors. This enrichment is particularly striking for lncRNAs that overlap with satellite repeats, a major component of centromeres. Consistently, we find increased non-coding RNA transcription from centromeres in tumors, in the majority of patients, suggesting that aberrant centromere activation takes place in HCC.

Impact of microRNAs on molecular epidemiology

2011 ◽  
Vol 152 (16) ◽  
pp. 633-641 ◽  
Author(s):  
Katalin Gőcze ◽  
Katalin Gombos ◽  
Gábor Pajkos ◽  
Ingrid Magda ◽  
Ágoston Ember ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Cancer Research ◽  
Molecular Epidemiology ◽  
Wide Spectrum ◽  
Translation Regulation ◽  
Rna Sequences ◽  
Serum Mirna ◽  
The Past ◽  
Non Coding Rna ◽  
Free Serum

Cancer research concerning short non-coding RNA sequences and functionally linked to RNA interference (RNAi) have reached explosive breakthrough in the past decade. Molecular technology applies microRNA in extremely wide spectrum from molecular tumor prediction, diagnostics, progression monitoring and prevention. Functional analysis of tissue miRNA and cell-free serum miRNA in posttranscription and translation regulation innovated and restructured the knowledge on the field. This review focuses on molecular epidemiology and primary prevention aspects of the small non-coding RNA sequences. Orv. Hetil., 2011, 152, 633–641.

Enzyme-Instructed Self-assembly in Biological Milieu for Theranostics Purpose

2019 ◽  
Vol 26 (8) ◽  
pp. 1351-1365 ◽  
Author(s):  
Zhentao Huang ◽  
Qingxin Yao ◽  
Simin Wei ◽  
Jiali Chen ◽  
Yuan Gao
Keyword(s):  
Small Molecules ◽  
Precision Medicine ◽  
Self Assembly ◽  
Public Healthcare ◽  
Enzymatic Conversion ◽  
Vaccine Adjuvants ◽  
New Paradigm ◽  
Cancer Treatments ◽  
The Past ◽  
Biological Milieu

Precision medicine is in an urgent need for public healthcare. Among the past several decades, the flourishing development in nanotechnology significantly advances the realization of precision nanomedicine. Comparing to well-documented nanoparticlebased strategy, in this review, we focus on the strategy using enzyme instructed selfassembly (EISA) in biological milieu for theranostics purpose. In principle, the design of small molecules for EISA requires two aspects: (1) the substrate of enzyme of interest; and (2) self-assembly potency after enzymatic conversion. This strategy has shown its irreplaceable advantages in nanomedicne, specifically for cancer treatments and Vaccine Adjuvants. Interestingly, all the reported examples rely on only one kind of enzymehydrolase. Therefore, we envision that the application of EISA strategy just begins and will lead to a new paradigm in nanomedicine.

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