Leveraging on nanomechanical sensors to single out active small ligands for beta2-microglobulin

A nanomechanical biosensor based on microcantilevers was implemented to test low molecular weight
(small) compounds for their ability to stabilize beta2-microglobulin (beta2-m) in its native conformation. Beta2-m
was immobilized on the top face of silicon microcantilevers and it was demonstrated that pH induced
unfolding of the immobilized beta2-m drives a specific microcantilever bending. This beta2-m microcantilever
assay was then implemented to probe the effect of a pilot set small ligands on beta2-m conformational
stability. Among the tested ligands, congo red was the only one able to protect beta2-m from unfolding,
that is known to be the primary trigger of its self-polymerization into fibrils and in turn of the onset
of amyloidosis. These findings disclose the high potentiality of nanomechanical sensors in the field of
protein conformation related diseases, as they bring the unique advantage of directly screening compounds
for their specific pharmacological activity rather than for generic binding preferences, effectively
shortcutting the identification of the active ones.