Rationally designed small molecules targeting toxic CAG repeat RNA that causes Huntington’s disease (HD) and spinocerebellar ataxia (SCAs).

Rationally designed small molecules targeting toxic CAG repeat RNA that causes Huntington’s disease (HD) and spinocerebellar ataxia (SCAs).

Publication date: May 07, 2019

Huntington’s diseases (HD) is a very devastating disease caused by r(CAG) expansion in HTT gene, encoding the huntingtin protein. r(CAG) expansion causes disease via multiple pathways including, 1) loss of normal protein function like sequestration of RNA binding protein such as Muscleblind-like (MBNL) and nucleolin, 2) Gain of function for mutant proteins and 3) repeat-associated non-ATG (RAN) translation; in which expanded r(CAG) translates into toxic poly glu, poly ser, or poly ala without the use of any canonical start codon. Herein, we have rationally designed and synthesized a unique class of pyridocoumarin derivatives that target the r(CAG) involved in HD and spinocerebellar ataxia (SCA) pathogenesis. Notably, compounds 3 and 15 showed higher affinity (nanomolar K) and selectivity for diseased r(CAG) RNA compared to regular duplex AU-paired RNA. Interestingly, both scaffolds are cell permeable, exhibit low toxicity to healthy fibroblast cells and are also capable of reducing the level of poly Q aggregation in cellular models. Indeed, our current study offers promising facet for selectively targeting repeats containing RNAs that cause severe diseases like HD and SCAs.

Khan, E., Biswas, S., Mishra, S.K., Mishra, R., Samanta, S., Mishra, A., Tawani, A., and Kumar, A. Rationally designed small molecules targeting toxic CAG repeat RNA that causes Huntington’s disease (HD) and spinocerebellar ataxia (SCAs). 06477. 2019 Biochimie.

Concepts Keywords
Affinity Drug Design
AU ATG
Duplex Huntingtin
Fibroblast Spinocerebellar ataxia
Gene Rare diseases
Huntingtin Protein Trinucleotide repeat disorder
Huntington Autosomal dominant disorders
Mutant Organ systems
Nanomolar Neurological disorders
Pathogenesis Huntington’s disease
RNA
Spinocerebellar Ataxia
Start Codon
Toxicity

Semantics

Type Source Name
drug DRUGBANK Alpha-Linolenic Acid
drug DRUGBANK Serine
drug DRUGBANK Glutamic Acid
pathway BSID Translation
gene UNIPROT RAN
gene UNIPROT MBNL1
drug DRUGBANK Ranitidine
disease MESH multiple
disease DOID spinocerebellar ataxia
gene UNIPROT HTT

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