scholarly journals Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy

2015 ◽  
Vol 10 (12) ◽  
pp. 2706-2715 ◽  
Author(s):  
Suzanne G. Rzuczek ◽  
Mark R. Southern ◽  
Matthew D. Disney
Keyword(s):  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Rna Toxicity ◽  
Small Molecule Library

scholarly journals Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules

2019 ◽  
Vol 20 (16) ◽  
pp. 4017 ◽  
Author(s):  
Kaalak Reddy ◽  
Jana R. Jenquin ◽  
John D. Cleary ◽  
J. Andrew Berglund
Keyword(s):  
Small Molecules ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Disease Onset ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Rna Toxicity ◽  
Complex Mechanisms ◽  
Potential Use

This review, one in a series on myotonic dystrophy (DM), is focused on the development and potential use of small molecules as therapeutics for DM. The complex mechanisms and pathogenesis of DM are covered in the associated reviews. Here, we examine the various small molecule approaches taken to target the DNA, RNA, and proteins that contribute to disease onset and progression in myotonic dystrophy type 1 (DM1) and 2 (DM2).

Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity

2017 ◽  
Author(s):  
Carolyn Bertozzi ◽  
Fred Tomlin ◽  
Ulla Gerling-Driessen ◽  
Yi-Chang Liu ◽  
Ryan Flynn ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Molecule ◽  
Proteasome Inhibitor ◽  
Activation Mechanism ◽  
Cancer Drugs ◽  
Small Molecule Library ◽  
Library Screen ◽  
In Cells

We discovered that the proteostasis modulating transcription factor Nrf1 requires cytosolic de-N-glycosylation by the N-glycanase NGly1 as part of its activation mechanism. Through a covalent small molecule library screen, we discovered an inhibitor of NGly1 that blocks Nrf1 activation in cells and potentiates the activity of proteasome inhibitor cancer drugs. The requirement of NGly1 for Nrf1 activity likely underlies several pathologies associated with a rare hereditary deficiency in NGly1.

scholarly journals A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

2016 ◽  
Vol 12 ◽  
pp. 125-138 ◽  
Author(s):  
Steven C Zimmerman
Keyword(s):  
Small Molecules ◽  
Supramolecular Chemistry ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Early Life ◽  
Rational Design ◽  
Early Experience ◽  
Therapeutic Agents ◽  
Early Career ◽  
Molecular Tweezers

This review summarizes part of the author’s research in the area of supramolecular chemistry, beginning with his early life influences and early career efforts in molecular recognition, especially molecular tweezers. Although designed to complex DNA, these hosts proved more applicable to the field of host–guest chemistry. This early experience and interest in intercalation ultimately led to the current efforts to develop small molecule therapeutic agents for myotonic dystrophy using a rational design approach that heavily relies on principles of supramolecular chemistry. How this work was influenced by that of others in the field and the evolution of each area of research is highlighted with selected examples.

Abstract 191: Deletion or Knockdown of Myotonic Dystrophy Protein Kinase Does Not Affect Cardiac Conduction or Ejection Fraction in Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Samuel Carrell ◽  
David Auerbach ◽  
Sanjay Pandey ◽  
Frank Bennett ◽  
Robert Dirksen ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Myotonic Dystrophy ◽  
Cardiac Conduction ◽  
Nuclear Retention ◽  
Rna Toxicity ◽  
Lv Dysfunction ◽  
Av Conduction ◽  
Myotonic Dystrophy Protein Kinase ◽  
Toxic Rna

Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, causes dominantly-inherited muscle weakness, defects of cardiac conduction, variable LV dysfunction, and risk of sudden death. The genetic basis is an expanded CTG repeat in the 3’ untranslated region of DMPK. DM1 patients are functionally hemizygous for DMPK protein, due to nuclear retention of mRNA having expanded repeats. The cardiac aspects are attributed to DMPK loss, toxicity of RNA with expanded repeats, or both. Dmpk heterozygous (+/-) and homozygous knockout (-/-) mice were reported to show AV conduction abnormalities resembling DM1 (Berul et al, JCI, 1999). In an effort to reduce RNA toxicity, antisense oligonucleotides (ASOs) targeting DMPK mRNA have recently entered clinical trials. DM1 phenotypes in skeletal muscle were corrected by ASO knockdown of toxic RNA in mice (Wheeler et al, Nature, 2012). While ASOs may have similar potential to mitigate RNA toxicity in the heart, there is risk of aggravated DMPK deficiency. To reexamine the role of DMPK in the conduction system we studied mice with Dmpk gene deletion or ASO knockdown. We obtained ECGs and echocardiograms on Dmpk -/- and +/- mice, compared to WT littermates. The +/- mice were treated with Dmpk-targeting ASOs or saline. Subcutaneous injection of 50 mg/kg/wk ASO was started at age 2 months, then shifted to biweekly injections after 6 weeks. Dmpk expression in hearts of +/- mice was ~50% of WT, and was further reduced by ASOs (84 ± 3% decrease of mRNA, 93 ± 2% decrease of protein, relative to WT). Surface ECGs and echocardiography at 6 and 10 months showed no differences of heart rate, cardiac conduction, or ejection fraction in WT, saline-treated +/-, ASO-treated +/-, or -/- mice. Conscious, unrestrained ECGs obtained at 11-12 months by radiotelemetry showed no differences among WT, saline-treated +/-, ASO-treated +/-, or -/- mice. We conclude that ASOs can induce posttranscriptional silencing of Dmpk in murine hearts. Constitutive absence of DMPK did not impact cardiac conduction or contractility, and the same was true for ASO knockdown to levels <15% of WT. Our data support the idea that cardiac dysfunction in DM1 results mainly from RNA toxicity, which potentially could be prevented or alleviated by ASOs.

scholarly journals Evaluation of ethyl N-(2-phenethyl) carbamate analogues as biofilm inhibitors of methicillin resistant Staphylococcus aureus

2016 ◽  
Vol 14 (28) ◽  
pp. 6853-6856 ◽  
Author(s):  
Matthew D. Stephens ◽  
Nisakorn Yodsanit ◽  
Christian Melander
Keyword(s):  
Staphylococcus Aureus ◽  
Small Molecule ◽  
Broad Spectrum ◽  
Biofilm Formation ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Small Molecule Library

A small molecule library consisting of 45 compounds was synthesized based on the bacterial metabolite ethylN-(2-phenethyl) carbamate. From this library, a more potent, broad-spectrum inhibitor of MRSA biofilm formation was discovered.

scholarly journals Age of Onset of RNA Toxicity Influences Phenotypic Severity: Evidence from an Inducible Mouse Model of Myotonic Dystrophy (DM1)

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e72907 ◽  
Author(s):  
Jordan T. Gladman ◽  
Mahua Mandal ◽  
Varadamurthy Srinivasan ◽  
Mani S. Mahadevan
Keyword(s):  
Mouse Model ◽  
Myotonic Dystrophy ◽  
Age Of Onset ◽  
Rna Toxicity

scholarly journals CHI PMUNK: A Virtual Synthesizable Small-Molecule Library for Medicinal Chemistry, Exploitable for Protein-Protein Interaction Modulators

ChemMedChem ◽  
2018 ◽  
Vol 13 (6) ◽  
pp. 532-539 ◽  
Author(s):  
Lina Humbeck ◽  
Sebastian Weigang ◽  
Till Schäfer ◽  
Petra Mutzel ◽  
Oliver Koch
Keyword(s):  
Small Molecule ◽  
Protein Interaction ◽  
Medicinal Chemistry ◽  
Protein Protein Interaction ◽  
Small Molecule Library

scholarly journals Discovery of PqsE Thioesterase Inhibitors for Pseudomonas aeruginosa Using DNA-Encoded Small Molecule Library Screening

2019 ◽  
Vol 15 (2) ◽  
pp. 446-456 ◽  
Author(s):  
Julie S. Valastyan ◽  
Michael R. Tota ◽  
Isabelle R. Taylor ◽  
Vasiliki Stergioula ◽  
Graham A. B. Hone ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Small Molecule ◽  
Library Screening ◽  
Small Molecule Library
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