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

• Published in: Biochimie Vol. 163; pp. 21 - 32
• Main Authors: Khan, Eshan, Biswas, Soumen, Mishra, Subodh Kumar, Mishra, Ribhav, Samanta, Sampak, Mishra, Amit, Tawani, Arpita, Kumar, Amit
• Format: Journal Article
• Language: English
• Published: France Elsevier B.V 01-08-2019
• Subjects: Drug design; Huntington's disease; Poly Q aggregation; RNA; Small molecules; Small molecules; Drug design; RNA; Huntington's disease; Poly Q aggregation
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2019.05.001

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.
•We have rationally designed and synthesized small molecules targeting mutant (CAG)exp RNA, the actual cause of HD disease.•Potential lead compounds exhibited high affinity (nanomolar Kd) and specificity with mutant (CAG)exp RNA.•Compounds aids to ameliorate the HD pathogenesis in cellular models.•Compounds treatments in patient derived cells alleviated the polyQ mediated cytotoxicity.