Identification of Plant-derived Alkaloids with Therapeutic Potential for Myotonic Dystrophy Type I.
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.
From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and.
Ruben
R
Herrendorff
the Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Maria Teresa
MT
Faleschini
From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and.
Adeline
A
Stiefvater
From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and.
Beat
B
Erne
From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and.
Tatiana
T
Wiktorowicz
From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and.
Frances
F
Kern
the Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Matthias
M
Hamburger
the Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Olivier
O
Potterat
From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and j.kinter@unibas.ch.
Jochen
J
Kinter
From the Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland and michael.sinnreich@unibas.ch.
Michael
M
Sinnreich
D020413:3' Untranslated Regions; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
D020413:3' Untranslated Regions; D000470:Alkaloids; D004268:DNA-Binding Proteins; C493663:MBNL1 protein, human; C479922:Mbnl1 protein, mouse; D016601:RNA-Binding Proteins
MBNL1; RNA splicing; RNA-protein interaction; alkaloids; myotonic dystrophy; natural product; non-coding RNA; trinucleotide repeat disease