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 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 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 DNA display of fragment pairs as a tool for the discovery of novel biologically active small molecules

2015 ◽  
Vol 6 (1) ◽  
pp. 739-744 ◽  
Author(s):  
J.-P. Daguer ◽  
C. Zambaldo ◽  
M. Ciobanu ◽  
P. Morieux ◽  
S. Barluenga ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Biologically Active ◽  
High Affinity ◽  
Affinity Ligand ◽  
High Affinity Ligand

A focused library for Hsp70 was prepared from fragments identified from an array combinatorially pairing two libraries of small molecule fragments. Screening of the focus library yielded high affinity ligand to Hsp70.

scholarly journals Small Molecule Analysis of Extracellular Vesicles Produced by Cryptococcus gattii: Identification of a Tripeptide Controlling Cryptococcal Infection in an Invertebrate Host Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Flavia C. G. Reis ◽  
Jonas H. Costa ◽  
Leandro Honorato ◽  
Leonardo Nimrichter ◽  
Taícia P. Fill ◽  
...  
Keyword(s):  
Small Molecules ◽  
Extracellular Vesicles ◽  
Small Molecule ◽  
Galleria Mellonella ◽  
Pathogenic Fungus ◽  
Cryptococcus Gattii ◽  
Biologically Active ◽  
Small Peptides ◽  
Cryptococcal Infection ◽  
Small Molecule Analysis

The small molecule (molecular mass <900 Daltons) composition of extracellular vesicles (EVs) produced by the pathogenic fungus Cryptococcus gattii is unknown, which limits the understanding of the functions of cryptococcal EVs. In this study, we analyzed the composition of small molecules in samples obtained from solid cultures of C. gattii by a combination of chromatographic and spectrometric approaches, and untargeted metabolomics. This analysis revealed previously unknown components of EVs, including small peptides with known biological functions in other models. The peptides found in C. gattii EVs had their chemical structure validated by chemical approaches and comparison with authentic standards, and their functions tested in a Galleria mellonella model of cryptococcal infection. One of the vesicular peptides (isoleucine-proline-isoleucine, Ile-Pro-Ile) improved the survival of G. mellonella lethally infected with C. gattii or C. neoformans. These results indicate that small molecules exported in EVs are biologically active in Cryptococcus. Our study is the first to characterize a fungal EV molecule inducing protection, pointing to an immunological potential of extracellular peptides produced by C. gattii.

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 Small molecule analysis of extracellular vesicles produced by Cryptococcus gattii: identification of a tripeptide controlling cryptococcal infection in an invertebrate host model

2021 ◽  
Author(s):  
Flavia C. G. Reis ◽  
Jonas H. Costa ◽  
Leandro Honorato ◽  
Leonardo Nimrichter ◽  
Taícia P. Fill ◽  
...  
Keyword(s):  
Small Molecules ◽  
Extracellular Vesicles ◽  
Small Molecule ◽  
Galleria Mellonella ◽  
Pathogenic Fungus ◽  
Cryptococcus Gattii ◽  
Biologically Active ◽  
Small Peptides ◽  
Cryptococcal Infection ◽  
Small Molecule Analysis

AbstractThe small molecule (molecular mass < 900 Daltons) composition of extracellular vesicles (EVs) produced by the pathogenic fungus Cryptococcus gattii is unknown, which limits the understanding of the functions of cryptococcal EVs. In this study, we analyzed the composition of small molecules in samples obtained from solid cultures of C. gattii by a combination of chromatographic and spectrometric approaches, and untargeted metabolomics. This analysis revealed previously unknown components of EVs, including small peptides with known biological functions in other models. The peptides found in C. gattii EVs had their chemical structure validated by chemical approaches and comparison with authentic standards, and their functions tested in a Galleria mellonella model of cryptococcal infection. One of the vesicular peptides (isoleucine-proline-isoleucine, Ile-Pro-Ile) improved the survival of G. mellonella lethally infected with C. gattii or C. neoformans. These results indicate that small molecules exported in EVs are biologically active in Cryptococcus. Our study is the first to characterize a fungal EV molecule inducing protection, pointing to an immunological potential of extracellular peptides produced by C. gattii.

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.

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