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

Khan, Eshan; Biswas, Soumen; Mishra, Subodh Kumar; Mishra, Ribhav; Samanta, Sampak; Mishra, Amit Kumar; Tawani, Arpita; Kumar, Amit

doi:10.1016/j.biochi.2019.05.001

Cited by 30 publications

(29 citation statements)

References 58 publications

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“…RNA sequences used for biophysical studies and gel retardation assay were prepared by runoff transcription method using synthetic DNA template as previously reported 36 . Briefly, synthetic DNA templates either amplified by PCR or cloned in a plasmid, were transcribed using T7 RNA polymerase, and transcribed products were purified by denaturing 15% PAGE.…”

Section: Methodsmentioning

confidence: 99%

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Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein

Khan

Mishra

et al. 2019

Sci Rep

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CAG repeats RNA causes various fatal neurodegenerative diseases exemplified by Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). Although there are differences in the pathogenic mechanisms, these diseases share the common cause, i.e., expansion of CAG repeats. The shared cause of these diseases raises the possibility for the exploiting the common target as a potential therapeutic approach. Oligonucleotide-based therapeutics are designed earlier with the help of the base pairing rule but are not very promiscuous, considering the nonspecific stimulation of the immune system and the poor cellular delivery. Therefore, small molecules-based therapeutics are preferred for targeting the repeats expansion disorders. Here, we have used the chemical similarity search approach to discern the small molecules that selectively target toxic CAG RNA. The lead compounds showed the specificity towards AA mismatch in biophysical studies including CD, ITC, and NMR spectroscopy and thus aided to forestall the polyQ mediated pathogenicity. Furthermore, the lead compounds also explicitly alleviate the polyQ mediated toxicity in HD cell models and patient-derived cells. These findings suggest that the lead compound could act as a chemical probe for AA mismatch containing RNA as well as plays a neuroprotective role in fatal neurodegenerative diseases like HD and SCAs.

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Section: Methodsmentioning

confidence: 99%

“…Fluorescence titration experiments were performed with multi-mode plate reader as previously described 36 . 10.0 μM of RNAs were serially diluted with the last well taken as a blank (No RNA).…”

Section: Methodsmentioning

confidence: 99%

Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein

Khan

Mishra

et al. 2019

Sci Rep

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“…Previous studies have reported that the stabilization of CGG repeat RNA via small molecule ameliorates FXTAS associated pathogenic defects (Yang et al, 2016b). Recently, our group has published few small molecules that thermodynamically stabilize expanded CAG RNA hairpin motifs which prevent polyQ aggregation in Huntington disorder (Khan et al, 2018(Khan et al, , 2019a. Herein, we have demonstrated that Curcumin binds to r(CGG) exp and potently reverses FXTASassociated pathogenic defects.…”

Section: Resultsmentioning

confidence: 81%

“…It is interesting to note that, spectral changes pattern were nearly similar during titration of Curcumin with all r(CGG) repeat RNAs which further suggested the similar mode of binding. Moreover, constant CD spectrum changes of CGG RNA elucidated the intercalation mode binding of Curcumin within CGG hairpin structure (Das et al, 2011;Khan et al, 2018Khan et al, , 2019a. Similarly, in melting studies, the increase in the melting temperature in presence of Curcumin depicts the stabilization of the targeted RNA structures.…”

Section: Discussionmentioning

confidence: 90%

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Curcumin Regulates the r(CGG)exp RNA Hairpin Structure and Ameliorate Defects in Fragile X-Associated Tremor Ataxia Syndrome

et al. 2020

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Fragile X-associated tremor ataxia syndrome is an untreatable neurological and neuromuscular disorder caused by unstable expansion of 55-200 CGG nucleotide repeats in 5 UTR of Fragile X intellectual disability 1 (FMR1) gene. The expansion of CGG repeats in the FMR1 mRNA elicits neuronal cell toxicity through two main pathogenic mechanisms. First, mRNA with CGG expanded repeats sequester specific RNA regulatory proteins resulting in splicing alterations and formation of ribonuclear inclusions. Second, repeat-associated non-canonical translation (RANT) of the CGG expansion produces a toxic homopolymeric protein, FMRpolyG. Very few small molecules are known to modulate these pathogenic events, limiting the therapeutic possibilities for FXTAS. Here, we found that a naturally available biologically active small molecule, Curcumin, selectively binds to CGG RNA repeats. Interestingly, Curcumin improves FXTAS associated alternative splicing defects and decreases the production and accumulation of FMRpolyG protein inclusion. Furthermore, Curcumin decreases cell cytotoxicity promptly by expression of CGG RNA in FXTAS cell models. In conclusion, our data suggest that small molecules like Curcumin and its derivatives may be explored as a potential therapeutic strategy against the debilitating repeats associated neurodegenerative disorders.

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Synthesis of Heterocycles in Nonconventional Bio‐based Reaction Media

Dolzhenko

2022

Heterocycles

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

Cited by 30 publications

References 58 publications

Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein

Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein

Curcumin Regulates the r(CGG)exp RNA Hairpin Structure and Ameliorate Defects in Fragile X-Associated Tremor Ataxia Syndrome

Synthesis of Heterocycles in Nonconventional Bio‐based Reaction Media

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