We report here the development of a family of small molecule binders that show selective binding to CAG-repeat RNA that causes Huntington’s Disease.1 The small molecules consisted of a bisamidinium core structure linked to two dimethylammonium units. Binding studies of the small molecules to CAG-repeat RNA using ITC showed strong binding strengths with Kd ranging from low micromolar to sub-micromolar levels, and suggested an entropy-driven binding. Molecular dynamics and NMR studies revealed that the small molecules act as groove binders and occupy the RNA major groove via extensive van der Waals and Columbic interactions.2

A library of derivatives with the bisamidinium core was synthesized and characterized for structure-activity relationship studies. Dimeric ligands constituting two binder units showed improved binding towards CAG-repeat RNA.3 Further functionalization of the small molecule binders with tetraphenylethylene as an AIE fluorophore resulted in potential theragnostic agents.4

References
Chan, H. Y. E. Front. Cell. Neurosci. 2014, 8.
Peng, S.; Guo, P.; Lin, X.; An, Y.; Sze, K. H.; Lau, M. H. Y.; Chen, Z. S.; Wang, Q.; Li, W.; Sun, J. K.-L.; Ma, S. Y.; Chan, T.-F.; Lau, K.-F.; Ngo, J. C. K.; Kwan, K. M.; Wong, C.-H.; Lam, S. L.; Zimmerman, S. C.; Tuccinardi, T.; Zuo, Z.; Au-Yeung, H. Y.; Chow, H.-M.; Chan, H. Y. E. CAG RNAs Induce DNA Damage and Apoptosis by Silencing NUDT16 Expression in Polyglutamine Degeneration. Proc. Natl. Acad. Sci. U. S. A. 2021, 118 (19). https://doi.org/10.1073/pnas.2022940118.
Luu, L. M.; Nguyen, L.; Peng, S.; Lee, J.; Lee, H. Y.; Wong, C.-H.; Hergenrother, P. J.; Chan, H. Y. E.; Zimmerman, S. C. ChemMedChem 2016, 11 (13), 1428–1435.
Zhang, R.; Kwok, R. T. K.; Tang, B. Z.; Liu, B. RSC Adv. 2015, 5 (36), 28332–28337.

Targeting Toxic RNA Repeats with Small Molecule Binders

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