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Rationally designed small molecules targeting toxic CAG repeat RNA that causes Huntington's disease (HD) and
Eshan Khan1, Soumen Biswas2, Subodh Kumar Mishra1
1Discipline of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India.
Insights
Researchers developed novel pyridocoumarin compounds targeting toxic RNA repeats in Huntington's disease (HD) and spinocerebellar ataxias (SCA). These compounds show high affinity, selectivity, low toxicity, and reduce harmful protein aggregation in cellular models.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Neurogenetics
Background:
- Huntington's disease (HD) and spinocerebellar ataxias (SCA) are severe neurodegenerative disorders.
- These diseases are caused by expanded r(CAG) repeats in specific genes, leading to toxic protein products.
- Current therapeutic strategies for these repeat expansion disorders are limited.
Purpose of the Study:
- To design and synthesize novel small molecules targeting the pathogenic r(CAG) repeats.
- To evaluate the affinity, selectivity, and cellular effects of these compounds in disease models.
- To explore a new therapeutic approach for HD and SCA by targeting disease-specific RNA structures.
Main Methods:
- Rational design and synthesis of pyridocoumarin derivatives.
- RNA binding assays to determine affinity (Kd) and selectivity against normal RNA duplexes.
- Cell permeability and cytotoxicity assays using fibroblast cell lines.
- Cellular models to assess the reduction of poly Q aggregation.
Main Results:
- Novel pyridocoumarin derivatives were synthesized, with compounds 3 and 15 showing high affinity (nanomolar Kd) for expanded r(CAG) RNA.
- These compounds demonstrated selectivity for diseased r(CAG)exp RNA over regular AU-paired RNA.
- The active compounds are cell-permeable, exhibit low toxicity in healthy cells, and effectively reduce poly Q aggregation in cellular models.
Conclusions:
- Pyridocoumarin derivatives represent a promising class of compounds for selectively targeting disease-causing RNA repeats.
- These findings offer a potential new therapeutic avenue for devastating neurodegenerative diseases like HD and SCA.
- Targeting expanded RNA repeats directly provides a unique strategy to combat these genetic disorders.
Abstract:
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)exp involved in HD and spinocerebellar ataxia (SCA) pathogenesis. Notably, compounds 3 and 15 showed higher affinity (nanomolar Kd) and selectivity for diseased r(CAG)exp 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.