preprints.org > biology and life sciences > biophysics > doi: 10.20944/preprints202404.0469.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Version 1 : Received: 4 April 2024 / Approved: 7 April 2024 / Online: 7 April 2024 (10:18:10 CEST)

An imbalance between production and excretion of amyloid β peptide (Aβ) in the brain tissues of Alzheimer’s disease (AD) patients leads to Aβ accumulation and formation of noxious Aβ oligomers/plaques. A promising approach to AD prevention is reduction of free Aβ level by directed enhancement of Aβ binding to its natural depot, human serum albumin (HSA). We previously demonstrated the ability of specific low-molecular-weight ligands (LMWLs) of HSA to improve its affinity for Aβ. Here we develop this approach by bioinformatic search for the clinically approved AD-related LMWLs of HSA, followed by classification of the candidates according to the predicted location of their binding sites on HSA surface, ranking of the candidates, and selective experimental validation of their impact on HSA affinity for Aβ. The top 100 candidate LMWLs were classified into the five clusters. The specific representatives of the different clusters exhibit dramatically different behavior, with 3- to 13-fold changes in equilibrium dissociation constants for the HSA-Aβ40 interaction: prednisone favors HSA-Aβ interaction, mefenamic acid shows the opposite effect, while levothyroxine exhibits the bidirectional effects. Overall, the LMWLs of HSA chosen here provide a basis for drug repurposing for AD prevention, and for search for the medications promoting AD progression.

Alzheimer’s disease; amyloid β peptide; human serum albumin; low-molecular-weight ligand; protein-ligand interaction; surface plasmon resonance spectroscopy

Biology and Life Sciences, Biophysics

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