scholarly journals Target-Directed Approaches for Screening Small Molecules against RNA Targets

2020 ◽  
Vol 25 (8) ◽  
pp. 869-894 ◽  
Author(s):  
Hafeez S. Haniff ◽  
Laurent Knerr ◽  
Jonathan L. Chen ◽  
Matthew D. Disney ◽  
Helen L. Lightfoot
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Drug Targets ◽  
Industrial Development ◽  
Rna Binding ◽  
Cellular Functions ◽  
Rna Molecules ◽  
The Face ◽  
Rna Binders ◽  
The Right

RNA molecules have a variety of cellular functions that can drive disease pathologies. They are without a doubt one of the most intriguing yet controversial small-molecule drug targets. The ability to widely target RNA with small molecules could be revolutionary, once the right tools, assays, and targets are selected, thereby defining which biomolecules are targetable and what constitutes drug-like small molecules. Indeed, approaches developed over the past 5–10 years have changed the face of small molecule–RNA targeting by addressing historic concerns regarding affinity, selectivity, and structural dynamics. Presently, selective RNA–protein complex stabilizing drugs such as branaplam and risdiplam are in clinical trials for the modulation of SMN2 splicing, compounds identified from phenotypic screens with serendipitous outcomes. Fully developing RNA as a druggable target will require a target engagement-driven approach, and evolving chemical collections will be important for the industrial development of this class of target. In this review we discuss target-directed approaches that can be used to identify RNA-binding compounds and the chemical knowledge we have today of small-molecule RNA binders.

scholarly journals Evolutionary meandering of intermolecular interactions along the drift barrier

2014 ◽  
Vol 112 (1) ◽  
pp. E30-E38 ◽  
Author(s):  
Michael Lynch ◽  
Kyle Hagner
Keyword(s):  
Intermolecular Interactions ◽  
Binding Sites ◽  
Rna Binding ◽  
Fine Tuning ◽  
Evolutionary Divergence ◽  
Sequence Motif ◽  
Cellular Functions ◽  
Mutation Pressure ◽  
Rna Molecules ◽  
The Face

Many cellular functions depend on highly specific intermolecular interactions, for example transcription factors and their DNA binding sites, microRNAs and their RNA binding sites, the interfaces between heterodimeric protein molecules, the stems in RNA molecules, and kinases and their response regulators in signal-transduction systems. Despite the need for complementarity between interacting partners, such pairwise systems seem to be capable of high levels of evolutionary divergence, even when subject to strong selection. Such behavior is a consequence of the diminishing advantages of increasing binding affinity between partners, the multiplicity of evolutionary pathways between selectively equivalent alternatives, and the stochastic nature of evolutionary processes. Because mutation pressure toward reduced affinity conflicts with selective pressure for greater interaction, situations can arise in which the expected distribution of the degree of matching between interacting partners is bimodal, even in the face of constant selection. Although biomolecules with larger numbers of interacting partners are subject to increased levels of evolutionary conservation, their more numerous partners need not converge on a single sequence motif or be increasingly constrained in more complex systems. These results suggest that most phylogenetic differences in the sequences of binding interfaces are not the result of adaptive fine tuning but a simple consequence of random genetic drift.

RNALigands: a database and web server for RNA - ligand interactions

RNA ◽  
2021 ◽  
pp. rna.078889.121
Author(s):  
Saisai Sun ◽  
Jianyi Yang ◽  
Zhaolei Zhang
Keyword(s):  
Secondary Structure ◽  
Small Molecules ◽  
Small Molecule ◽  
Neurological Diseases ◽  
Experimental Studies ◽  
Rna Structures ◽  
Structural Motifs ◽  
Rna Molecules ◽  
Small Molecule Ligands ◽  
Ligand Interactions

Motivation: RNA molecules can fold into complex and stable 3-D structures, allowing them to carry out important genetic, structural, and regulatory roles inside the cell. These complex structures often contain 3-D pockets made up of secondary structural motifs that can be potentially targeted by small molecule ligands. Indeed, many RNA structures in PDB contain bound small molecules, and high-throughput experimental studies have generated large number of interacting RNA and ligand pairs. There are considerable interests in developing small molecule lead compounds targeting viral RNAs or those RNAs implicated in neurological diseases or cancer. Results: We hypothesize that RNAs that have similar secondary structural motifs may bind to similar small molecule ligands. Towards this goal, we established a database collecting RNA secondary structural motifs and bound small molecules ligands. We further developed a computational pipeline, which takes input an RNA sequence, predicts its secondary structure, extracts structural motifs and searches the database for similar secondary structure motifs and interacting small molecules. We demonstrated the utility of the server by querying α-synuclein mRNA 5′ UTR sequence and finding potential matches which was validated as correct. Availability and Implementation: The server is publicly available at http://RNALigands.ccbr.utoronto.ca. The source code can also be downloaded at https://github.com/SaisaiSun/RNALigands.

scholarly journals Discovery of RNA Binding Small Molecules Using Small Molecule Microarrays

2016 ◽  
pp. 157-175 ◽  
Author(s):  
Colleen M. Connelly ◽  
Fardokht A. Abulwerdi ◽  
John S. Schneekloth
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Rna Binding

scholarly journals Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like Chemical Space

2019 ◽  
Vol 25 (4) ◽  
pp. 384-396 ◽  
Author(s):  
Noreen F. Rizvi ◽  
John P. Santa Maria ◽  
Ali Nahvi ◽  
Joel Klappenbach ◽  
Daniel J. Klein ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Small Molecules ◽  
Small Molecule ◽  
Rna Binding ◽  
Chemical Space ◽  
Chemical Properties ◽  
Identification System ◽  
Specific Chemical ◽  
Ligand Identification ◽  
Molecule Interactions

Although the potential value of RNA as a target for new small molecule therapeutics is becoming increasingly credible, the physicochemical properties required for small molecules to selectively bind to RNA remain relatively unexplored. To investigate the druggability of RNAs with small molecules, we have employed affinity mass spectrometry, using the Automated Ligand Identification System (ALIS), to screen 42 RNAs from a variety of RNA classes, each against an array of chemically diverse drug-like small molecules (~50,000 compounds) and functionally annotated tool compounds (~5100 compounds). The set of RNA–small molecule interactions that was generated was compared with that for protein–small molecule interactions, and naïve Bayesian models were constructed to determine the types of specific chemical properties that bias small molecules toward binding to RNA. This set of RNA-selective chemical features was then used to build an RNA-focused set of ~3800 small molecules that demonstrated increased propensity toward binding the RNA target set. In addition, the data provide an overview of the specific physicochemical properties that help to enable binding to potential RNA targets. This work has increased the understanding of the chemical properties that are involved in small molecule binding to RNA, and the methodology used here is generally applicable to RNA-focused drug discovery efforts.

scholarly journals Identification of Biologically Active, HIV TAR RNA-Binding Small Molecules Using Small Molecule Microarrays

2014 ◽  
Vol 136 (23) ◽  
pp. 8402-8410 ◽  
Author(s):  
Joanna Sztuba-Solinska ◽  
Shilpa R. Shenoy ◽  
Peter Gareiss ◽  
Lauren R. H. Krumpe ◽  
Stuart F. J. Le Grice ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Rna Binding ◽  
Biologically Active ◽  
Tar Rna

scholarly journals An in silico map of the SARS-CoV-2 RNA Structurome

2020 ◽  
Author(s):  
Ryan J. Andrews ◽  
Jake M. Peterson ◽  
Hafeez S. Haniff ◽  
Jonathan Chen ◽  
Christopher Williams ◽  
...  
Keyword(s):  
Small Molecules ◽  
Rna Structure ◽  
Drug Targets ◽  
Rna Binding ◽  
Rna Virus ◽  
Human Pathogens ◽  
Public Database ◽  
Positive Sense ◽  
Basic Biology ◽  
Potential Drug Targets

AbstractSARS-CoV-2 is a positive-sense single-stranded RNA virus that has exploded throughout the global human population. This pandemic coronavirus strain has taken scientists and public health researchers by surprise and knowledge of its basic biology (e.g. structure/function relationships in its genomic, messenger and template RNAs) and modes for therapeutic intervention lag behind that of other human pathogens. In this report we used a recently-developed bioinformatics approach, ScanFold, to deduce the RNA structural landscape of the SARS-CoV-2 transcriptome. We recapitulate known elements of RNA structure and provide a model for the folding of an essential frameshift signal. Our results find that the SARS-CoV-2 is greatly enriched in unusually stable and likely evolutionarily ordered RNA structure, which provides a huge reservoir of potential drug targets for RNA-binding small molecules. Our results also predict regions that are accessible for intermolecular interactions, which can aid in the design of antisense therapeutics. All results are made available via a public database (the RNAStructuromeDB) where they may hopefully drive drug discovery efforts to inhibit SARS-CoV-2 pathogenesis.

scholarly journals Systematic analysis of the interactions driving small molecule–RNA recognition

2020 ◽  
Vol 11 (7) ◽  
pp. 802-813 ◽  
Author(s):  
G. Padroni ◽  
N. N. Patwardhan ◽  
M. Schapira ◽  
A. E. Hargrove
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Small Molecule ◽  
Rna Binding ◽  
Rna Recognition ◽  
Systematic Analysis

This study underscores privileged interactions for RNA binding small molecules, an emerging focus in drug discovery.

scholarly journals Proof of concept continuous event logging in living cells

2017 ◽  
Author(s):  
Andrey Shur ◽  
Richard M. Murray
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Dna Sequences ◽  
Rna Binding ◽  
Attachment Site ◽  
Genetic Circuit ◽  
Genetic Changes ◽  
Guide Rna ◽  
Molecular Events ◽  
Long Read

AbstractCells must detect and respond to molecular events such as the presence or absence of specific small molecules. To accomplish this, cells have evolved methods to measure the presence and concentration of these small molecules in their environment and enact changes in gene expression or behavior. However, cells don’t usually change their DNA in response to such outside stimuli. In this work, we have engineered a genetic circuit that can enact specific and controlled genetic changes in response to changing small molecule concentrations. Known DNA sequences can be repeatedly integrated into a genomic array such that their identity and order encodes information about past small molecule concentrations that the cell has experienced. To accomplish this, we use catalytically inactive CRISPR-Cas9 (dCas9) to bind to and block attachment sites for the integrase Bxb1. Therefore, through the co-expression of dCas9 and guide RNA, Bxb1 can be directed to integrate one of two engineered plasmids, which correspond to two orthogonal small molecule inducers that can be recorded with this system. We identified the optimal location of guide RNA binding to the Bxb1 attP integrase attachment site, and characterized the detection limits of the system by measuring the minimal small molecule concentration and shortest induction time necessary to produce measurable differences in array composition as read out by Oxford Nanopore long read sequencing technology.

THE ROLE OF THE CIVIL SERVICE IN THE INDUSTRIALIZATION OF NIGERIA

2018 ◽  
Vol 1 (2) ◽  
Author(s):  
Chiemeka Onyema
Keyword(s):  
Public Service ◽  
Industrial Development ◽  
Industrial Revolution ◽  
National Development ◽  
Public Servants ◽  
Business Policy ◽  
Technological Base ◽  
Development Plans ◽  
Ease Of Doing Business ◽  
The Right

The goal of berthing Nigeria’s full-scale industrial revolution is yet to be achieved. All the industrial development plans have so far failed to accelerate the nation’s industrialization, hence the country’s low industrial base which has kept her in the league of developing nations. In fact, Nigeria has in recent times been experiencing deindustrialization, as several industries have collapsed and some others, such as Unilever and Michelin, have relocated to other countries. Several factors are responsible for Nigeria’s low industrial development and they include: inadequate infrastructure (particularly, energy), poor technological base, multiple taxes and levies, and, the shortage and high cost of foreign exchange. Despite a growing body of literature on industrialization in Nigeria, not much has been written about the link between Public Service Reforms and industrialization in Nigeria. This paper examines the links between the implementation of the Service Compact (SERVICOM) Charter and the achievement of Nigeria’s industrial development policies, especially the ‘Ease of Doing Business’ Policy. The paper makes the case that the goal of industrializing Nigeria will not be fully realised without an efficient Public Service. Furthermore, the paper highlights the need for Nigerian public servants to have the right work attitude, and to be morally upright and patriotic, in order to create a business-friendly environment and to build investor confidence, so as to facilitate and accelerate the country’s industrialization and overall national development. The author recommends that the Nigerian government should strengthen the implementation of the Servicom Charter and also incorporate the Charter into the industrialization plan.

scholarly journals Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance

2017 ◽  
Vol 24 (10) ◽  
pp. R349-R366 ◽  
Author(s):  
Catherine Zabkiewicz ◽  
Jeyna Resaul ◽  
Rachel Hargest ◽  
Wen Guo Jiang ◽  
Lin Ye
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Bone Morphogenetic Proteins ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Breast Tumour ◽  
Cellular Functions ◽  
Foetal Development ◽  
Key Factor ◽  
The Right

Bone morphogenetic proteins (BMPs) belong to the TGF-β super family, and are essential for the regulation of foetal development, tissue differentiation and homeostasis and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which studies have revealed aberrations of both BMP expression and signalling, which correlate clinically with breast cancer progression. Ultimately a BMP profile could provide new prognostic disease markers. As the evidence suggests a role for BMPs in regulating breast tumour cellular function, in particular interactions with tumour stroma and the bone metastatic microenvironment, there may be novel therapeutic potential in targeting BMP signalling in breast cancer. This review provides an update on the current knowledge of BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease-specific bone metastasis.

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