nTRD22

nTRD22 is an RNA-binding allosteric modulator targeting TDP-43. nTRD22 binds to the N-terminal domain of TDP-43, thereby allosterically regulating the RNA-binding domain of TDP-43 and reducing its RNA-binding ability. nTRD22 decreases the TDP-43 protein level in primary motor neurons. nTRD22 alleviates motor dysfunction in amyotrophic lateral sclerosis models. nTRD22 is applicable to related research on amyotrophic lateral sclerosis ^[1].

In Vivo, nTRD22 (50 μM; mixed in diet) significantly alleviates motor deficits in an ALS Drosophila model, with a more prominent rescue effect observed in aged Drosophila^[1].

In Vitro, nTRD22 (0.03 μM-1 mM) binds to full-length TDP-431-260 with an apparent Kd of 145 ± 3 μM and to the isolated N-terminal domain TDP-431-102 with an apparent Kd of 96 ± 36 μM^[1]. nTRD22 inhibits TDP-431-260 binding to UG6 RNA with an IC₅₀ of ~100 μM in an alpha assay^[1]. nTRD22 (0.1-500 μM) inhibits TDP-431-260 binding to (UG)6 RNA with an IC₅₀ of ~145 μM and achieves ~30% inhibition of the interaction in an SPR assay^[1].

References:
[1]. Mollasalehi N, et al. An Allosteric Modulator of RNA Binding Targeting the N-Terminal Domain of TDP-43 Yields Neuroprotective Properties. ACS Chem Biol. 2020;15(11):2854-2859.