Author Identifier (ORCID)
Ajish Ariyath: https://orcid.org/0000-0003-1611-2990
Fraulein Denise Arigo: https://orcid.org/0009-0009-5169-0199
W. M.A.D.Binosha Fernando: https://orcid.org/0000-0002-8364-7808
Ralph N. Martins: https://orcid.org/0000-0002-4828-9363
Prashant Bharadwaj: https://orcid.org/0000-0003-4361-9906
Abstract
Dysregulation of the deubiquitinating enzyme Ubiquitin-specific peptidase 14 (USP14) is implicated in several neurodegenerative diseases, and IU1, an allosteric inhibitor, has shown neuroprotective effects by reducing protein aggregate toxicity. This study aimed to develop new IU1 analogues and evaluate their ability to mitigate amyloid-β (Aβ) accumulation and toxicity in Alzheimer’s disease (AD) cell and Caenorhabditis elegans worm models. IU1 and 71 newly designed analogues identified using the AtomNet® virtual screening platform were assessed in an amyloid precursor protein-C terminal fragment/amyloid-β (APP-C99/Aβ)-producing AD cell model using a high-throughput toxicity assay. Lead compounds were further evaluated for their effects on neurodegeneration, behaviour, and survival. IU1 reduced Aβ-mediated toxicity and neurodegeneration in cell and worm models. Of the 71 analogues predicted to bind ubiquitin-specific peptidase 14 (USP14), two compounds, AA10 and AA51, showed >50% rescue of Aβ-induced toxicity and robust enhancement of autophagy and proteasome activity. In Caenorhabditis elegans, both compounds alleviated glutamatergic neuron loss and rescued behavioural impairments. IU1 and analogues exhibit protective effects against Aβ toxicity in AD models. Analogues AA10 and AA51 showed greater potency than IU1 and effectively enhanced proteostasis pathways. These findings support USP14 as a promising therapeutic target and provide a basis for the development of improved IU1-derived compounds for AD and related disorders.
Keywords
Amyloid precursor protein, amyloid-β protein, artificial intelligence, deubiquitinase enzyme, ubiquitin–proteasome system
Document Type
Journal Article
Date of Publication
2-1-2026
Volume
27
Issue
4
PubMed ID
41752099
Publication Title
International Journal of Molecular Sciences
Publisher
MDPI
School
Centre of Excellence for Alzheimer's Disease Research and Care / School of Medical and Health Sciences
Funders
NHMRC-ARC Dementia Research Development Fellowship / National Foundation for Medical Research and Innovation
Grant Number
NHMRC-ARC Number : APP1107109
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Ariyath, A., Arigo, F. D., Wallach, I., Fernando, W. M. a. D. B., Martins, R. N., & Bharadwaj, P. (2026). Novel Small-Molecule analogues of IU1 ameliorate amyloid-Β mediated toxicity in Alzheimer’s disease cell and worm models. International Journal of Molecular Sciences, 27(4), 1963. https://doi.org/10.3390/ijms27041963