Drug Repositioning Targeting Glutaminase Reveals Drug Candidates for The Treatment of Alzheimer’s Disease Patients

Abstract

Background
Despite numerous clinical trials and decades of endeavour, there is still no effective cure for Alzheimer’sdisease. Computational drug repositioning approaches may be employed for the development of new treatmentstrategies for Alzheimer’s patients since an extensive amount of omics data has been generated during pre-clinicaland clinical studies. However, targeting the most critical pathophysiological mechanisms and determining drugswith proper pharmacodynamics and good efficacy are equally crucial in drug repurposing and often imbalanced inAlzheimer’s studies.

Methods
Here, we investigated central co-expressed genes upregulated in Alzheimer’s disease to determine aproper therapeutic target. We backed our reasoning by checking the target gene’s estimated non-essentiality forsurvival in multiple human tissues. We screened transcriptome profiles of various human cell lines perturbed by druginduction (for 6798 compounds) and gene knockout using data available in the Connectivity Map database. Then,we applied a profile-based drug repositioning approach to discover drugs targeting the target gene based on thecorrelations between these transcriptome profiles. We evaluated the bioavailability, functional enrichment profilesand drug-protein interactions of these repurposed agents and evidenced their cellular viability and efficacy in glialcell culture by experimental assays and Western blotting. Finally, we evaluated their pharmacokinetics to anticipate towhich degree their efficacy can be improved.

Results
We identified glutaminase as a promising drug target. Glutaminase overexpression may fuel the glutamateexcitotoxicity in neurons, leading to mitochondrial dysfunction and other neurodegeneration hallmark processes.The computational drug repurposing revealed eight drugs: mitoxantrone, bortezomib, parbendazole, crizotinib,withaferin-a, SA-25547 and two unstudied compounds. We demonstrated that the proposed drugs could effectivelysuppress glutaminase and reduce glutamate production in the diseased brain through multiple neurodegenerationassociatedmechanisms, including cytoskeleton and proteostasis. We also estimated the human blood–brain barrierpermeability of parbendazole and SA-25547 using the SwissADME tool.

Conclusions
This study method effectively identified an Alzheimer’s disease marker and compounds targeting themarker and interconnected biological processes by use of multiple computational approaches. Our results highlightthe importance of synaptic glutamate signalling in Alzheimer’s disease progression. We suggest repurposable drugs