scholarly journals Targeting RNA structures in diseases with small molecules

2020 ◽  
Vol 64 (6) ◽  
pp. 955-966 ◽  
Author(s):  
Yanqiu Shao ◽  
Qiangfeng Cliff Zhang
Keyword(s):  
Gene Expression ◽  
Molecular Biology ◽  
Small Molecules ◽  
Structural Biology ◽  
Rna Structure ◽  
Therapeutic Potential ◽  
Rna Structures ◽  
Gene Expression And Regulation ◽  
Cellular Processes ◽  
Target Rna

Abstract RNA is crucial for gene expression and regulation. Recent advances in understanding of RNA biochemistry, structure and molecular biology have revealed the importance of RNA structure in cellular processes and diseases. Various approaches to discovering drug-like small molecules that target RNA structure have been developed. This review provides a brief introduction to RNA structural biology and how RNA structures function as disease regulators. We summarize approaches to targeting RNA with small molecules and highlight their advantages, shortcomings and therapeutic potential.

Quantitative Structure Activity Relationship (QSAR) study predicts small molecule binding to RNA structure

2021 ◽  
Author(s):  
Zhengguo Cai ◽  
Martina Zafferani ◽  
Olanrewaju Akande ◽  
Amanda Hargrove
Keyword(s):  
High Resolution ◽  
Small Molecules ◽  
Small Molecule ◽  
Rna Structure ◽  
Quantitative Structure ◽  
Rna Structures ◽  
Qsar Study ◽  
Structure Activity ◽  
Qsar Models ◽  
Hiv 1

The diversity of RNA structural elements and their documented role in human diseases make RNA an attractive therapeutic target. However, progress in drug discovery and development has been hindered by challenges in the determination of high-resolution RNA structures and a limited understanding of the parameters that drive RNA recognition by small molecules, including a lack of validated quantitative structure-activity relationships (QSAR). Herein, we developed QSAR models that quantitatively predict both thermodynamic and kinetic-based binding parameters of small molecules and the HIV-1 TAR model RNA system. A set of small molecules bearing diverse scaffolds was screened against the HIV-1-TAR construct using surface plasmon resonance, which provided the binding kinetics and affinities. The data was then analyzed using multiple linear regression (MLR) combined with feature selection to afford robust models for binding of diverse RNA-targeted scaffolds. The predictivity of the model was validated on untested small molecules. The QSAR models presented herein represent the first application of validated and predictive 2D-QSAR using multiple scaffolds against an RNA target. We expect the workflow to be generally applicable to other RNA structures, ultimately providing essential insight into the small molecule descriptors that drive selective binding interactions and, consequently, providing a platform that can exponentially increase the efficiency of ligand design and optimization without the need for high-resolution RNA structures.

scholarly journals Small molecule targeting r(UGGAA)n disrupts RNA foci and alleviates disease phenotype in Drosophila model

2020 ◽  
Author(s):  
Tomonori Shibata ◽  
Konami Nagano ◽  
Morio Ueyama ◽  
Kensuke Ninomiya ◽  
Tetsuro Hirose ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Rna Structure ◽  
Therapeutic Potential ◽  
Spinocerebellar Ataxia Type ◽  
Disease Phenotype ◽  
Rna Foci ◽  
Drosophila Model ◽  
Biological Studies ◽  
And Function

AbstractSynthetic small molecules modulating RNA structure and function have therapeutic potential for RNA diseases. Here we report our discovery that naphthyridine carbamate dimer (NCD) targets disease-causing r(UGGAA)n repeat RNAs in spinocerebellar ataxia type 31 (SCA31). Structural analysis of the NCD-UGGAA/UGGAA complex by nuclear magnetic resonance (NMR) spectroscopy clarified the mode of binding that recognizes four guanines in UGGAA/UGGAA pentad by hydrogen bonding with four naphthyridine moieties of two NCD molecules. Biological studies show that NCD disrupts naturally occurring RNA foci built on r(UGGAA)n repeat RNA known as nuclear stress bodies (nSBs) by interfering with RNA-protein interactions resulting in the suppression of nSBs-mediated splicing event. Feeding NCD to larvae of the Drosophila model of SCA31 alleviates disease phenotype induced by toxic r(UGGAA)n repeat RNA. These studies demonstrated that small molecules targeting toxic repeat RNAs are a promising chemical tool for studies on repeat expansion diseases.

Along the Central Dogma—Controlling Gene Expression with Small Molecules

2018 ◽  
Vol 87 (1) ◽  
pp. 391-420 ◽  
Author(s):  
Tilman Schneider-Poetsch ◽  
Minoru Yoshida
Keyword(s):  
Gene Expression ◽  
Molecular Biology ◽  
Small Molecules ◽  
Small Molecule ◽  
Sequencing Technology ◽  
Disease Treatment ◽  
Modern Biology ◽  
Central Dogma ◽  
Cellular Effects ◽  
Important Regulator

The central dogma of molecular biology, that DNA is transcribed into RNA and RNA translated into protein, was coined in the early days of modern biology. Back in the 1950s and 1960s, bacterial genetics first opened the way toward understanding life as the genetically encoded interaction of macromolecules. As molecular biology progressed and our knowledge of gene control deepened, it became increasingly clear that expression relied on many more levels of regulation. In the process of dissecting mechanisms of gene expression, specific small-molecule inhibitors played an important role and became valuable tools of investigation. Small molecules offer significant advantages over genetic tools, as they allow inhibiting a process at any desired time point, whereas mutating or altering the gene of an important regulator would likely result in a dead organism. With the advent of modern sequencing technology, it has become possible to monitor global cellular effects of small-molecule treatment and thereby overcome the limitations of classical biochemistry, which usually looks at a biological system in isolation. This review focuses on several molecules, especially natural products, that have played an important role in dissecting gene expression and have opened up new fields of investigation as well as clinical venues for disease treatment.

scholarly journals Rethinking the bioavailability and cellular transport properties of S-adenosylmethionine

Cell Stress ◽  
2021 ◽  
Vol 6 (1) ◽  
pp. 1-5
Author(s):  
Yudong Sun ◽  
Jason W. Locasale
Keyword(s):  
Gene Expression ◽  
Plasma Membrane ◽  
Transport Properties ◽  
Therapeutic Potential ◽  
Cellular Transport ◽  
Over The Counter ◽  
Cellular Processes ◽  
Nutrient Supplement ◽  
Wide Range ◽  
Cellular Permeability

S-adenosylmethionine (SAM) is a versatile metabolite that participates in a wide range of reactions such as methylation and transsulfuration. These capabilities allow SAM to influence cellular processes such as gene expression and redox balancing. The importance of SAM is highlighted by its widespread usage as an over-the-counter nutrient supplement and as an experimental reagent in molecular biology. The bioavailability and cellular transport properties of SAM, however, are often overlooked under these contexts, putting limits on SAM’s therapeutic potential and complicating the interpretation of experimental results. In this article, we examined the chemical stability and cellular permeability of SAM, proposed a schematic for indirect SAM transport across the mammalian plasma membrane, and lastly discussed the implications arising from such transport schematic.

scholarly journals The Biomarker and Therapeutic Potential of Circular Rnas in Schizophrenia

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2238
Author(s):  
Artem Nedoluzhko ◽  
Natalia Gruzdeva ◽  
Fedor Sharko ◽  
Sergey Rastorguev ◽  
Natalia Zakharova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Circular Rna ◽  
Circular Rnas ◽  
Cellular Processes ◽  
Non Coding Rna

Circular RNAs (circRNAs) are endogenous, single-stranded, most frequently non-coding RNA (ncRNA) molecules that play a significant role in gene expression regulation. Circular RNAs can affect microRNA functionality, interact with RNA-binding proteins (RBPs), translate proteins by themselves, and directly or indirectly modulate gene expression during different cellular processes. The affected expression of circRNAs, as well as their targets, can trigger a cascade of events in the genetic regulatory network causing pathological conditions. Recent studies have shown that altered circular RNA expression patterns could be used as biomarkers in psychiatric diseases, including schizophrenia (SZ); moreover, circular RNAs together with other cell molecules could provide new insight into mechanisms of this disorder. In this review, we focus on the role of circular RNAs in the pathogenesis of SZ and analyze their biomarker and therapeutic potential in this disorder.

scholarly journals The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2106 ◽  
Author(s):  
Jacopo Boni ◽  
Carlota Rubio-Perez ◽  
Nuria López-Bigas ◽  
Cristina Fillat ◽  
Susana de la Luna
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Small Molecules ◽  
Clinical Implications ◽  
Hallmarks Of Cancer ◽  
Cellular Processes ◽  
Tumor Onset ◽  
Dual Specificity ◽  
Cancer Initiation

DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available.

scholarly journals Current production as a rapid response expression reporter under micro-oxic and anoxic conditions

2018 ◽  
Author(s):  
Cody Madsen ◽  
Noelia Barvo ◽  
Ciara Fromwiller ◽  
Serenity Tyll ◽  
Brian Amburn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Biology ◽  
Electricity Production ◽  
Michigan State University ◽  
State University ◽  
Anoxic Conditions ◽  
Cellular Processes ◽  
Competing Interests ◽  
Current Production ◽  
Response Expression

AbstractInducible gene expression is crucial for regulating cellular processes and production of compounds within cellular pathways. Yet, inducing gene expression is only the first step to utilizing cellular processes for an applied purpose such as biosensors. Detecting when gene expression occurs is central to understanding the overall mechanism of the process as well as maximizing the process. Fluorescent proteins have been established as the primary tool for detecting gene expression in inducible systems. This study proposes electricity production as an alternate tool in reporting gene expression. Using a model organism for electricity production, Shewanella oneidensis MR-1, current was shown to be an efficient reporter for gene expression and comparable to superfolder green fluorescent protein (GFP). Through regulation of the lac operator and T7 promoter, current production was induced by isopropyl β-D-1-thiogalactopyranoside (IPTG) addition. IPTG addition induced translation of GFP and the MtrB protein, which complemented a ∆mtrB strain of S. oneidensis MR-1 and restored current production. This inducible system generated reproducible current in 18 minutes in both micro-oxic and anoxic conditions. These results show that current is a fast reporter for gene expression.Financial DisclosureThe team was supported by the following departments and colleges at Michigan State University: College of Natural Science, College of Engineering, Biochemistry and Molecular Biology Department and Plant Research Laboratory. The team also received support from the DOE Great Lakes Bioenergy Research Center (DOE Office of Science BER DE-FC02-07ER64494) and startup funding from the Department of Molecular Biology and Biochemistry, Michigan State University and support from Michigan State University AgBioResearch (MICL02454) (to B.H.). This work was also supported by NSF CAREER (Award #1254238) to T.A.W. MSU Alpha Chi Sigma also supported the team.Competing InterestsThe authors declare that no competing interests exist.Ethics StatementN/AData AvailabilityAll data will be supplied upon request by the corresponding author.This work was assessed during the iGEM/PLOS Realtime Peer Review Jamboree on 23rd February 2018 and has been revised in response to the reviewers’ comments.

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