Tyrosine Peptides Alleviates Multifaceted Toxicity Linked to Expanded CGG Repeats in Fragile X‑Associated...

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)/Fragile X-associated Primary Ovarian Insufficiency (FXPOI) are conditions caused by an elevated level of CGG repeats in the 5' untranslated region (5'-UTR) of the Fragile X Mental Retardation 1 (FMR1) gene. These trinucleotide extended RNA repeats [r-(CGG)_exp] produce toxic homopolymeric proteins in neuronal cells via repeat-associated non-ATG (RAN) translation or formation of RNA foci. A promising therapeutic approach for such conditions involves identifying potent modulators, particularly those with high binding affinity and selectivity toward these expanded RNA repeats. We investigated the therapeutic potential of homoaromatic tyrosine peptides (2Y, 3Y, and 4Y) toward CGG repeat RNA by employing biophysical and cell model-based studies. Furthermore, administering the peptides from the early developmental stages in the Drosophila model of FXTAS also mitigated the disease symptoms. Results revealed that the peptides interact with r-(CGG)_exp in a thermodynamically advantageous manner and are highly selective for the GG-rich RNA motif. All three peptides correct alternative splicing flaws linked to FXTAS, reduce the synthesis and buildup of the FMR1polyG protein inclusion, and rapidly suppress cell cytotoxicity in both the cellular and Drosophila models. These findings show that homo aromatic tyrosine-based peptides targeting treacherous repeat RNAs are potential therapeutic tools for treating FXTAS/FXPOI.