Leveraging on nanomechanical sensors to single out active small ligands for β2-microglobulin

A nanomechanical biosensor based on microcantilevers was implemented to test low molecular weight (small) compounds for their ability to stabilize β2-microglobulin (β2-m) in its native conformation. β2-m was immobilized on the top face of silicon microcantilevers and it was demonstrated that pH induced unfolding of the immobilized β2-m drives a specific microcantilever bending. This β2-m microcantilever assay was then implemented to probe the effect of a pilot set small ligands on β2-m conformational stability. Among the tested ligands, congo red was the only one able to protect β2-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.