Identification of plant-derived alkaloids with therapeutic potential for myotonic dystrophy type I
| Autor: | Beat Erne, Maria Teresa Faleschini, Jochen Kinter, Frances Kern, Tatiana Wiktorowicz, Michael Sinnreich, Matthias Hamburger, Ruben Herrendorff, Olivier Potterat, Adeline Stiefvater |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Drug Evaluation Preclinical Biology 010402 general chemistry 01 natural sciences Biochemistry Myotonic dystrophy Models Biological Cell Line 03 medical and health sciences chemistry.chemical_compound Mice Alkaloids medicine MBNL1 Animals Humans Myotonic Dystrophy Molecular Biology 3' Untranslated Regions Natural product Drug discovery Alternative splicing RNA RNA-Binding Proteins Molecular Bases of Disease Cell Biology Non-coding RNA medicine.disease 0104 chemical sciences 3. Good health DNA-Binding Proteins Alternative Splicing 030104 developmental biology chemistry RNA splicing Trinucleotide Repeat Expansion |
| Zdroj: | The Journal of biological chemistry |
| Popis: | Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3′ UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of available MBNL1 leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequestered MBNL1 from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1. We identified several alkaloids, including the β-carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of the DM1 pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases. |
| Databáze: | OpenAIRE |
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