Structural Stabilization of Clinically Oriented Oligomeric Proteins During their Transit through Synthetic Secretory Amyloids

JULIETA M. SANCHEZ; HECTOR LOPEZ LAGUNA; ELOI PARLADE; ANGELA DI SOMMA; ANDREA L. LIVIERI; RAMON MANGUES; PATRICIA ÁLAMO; UGUTZ UNZUETA ,; ANTONIO VILLAVERDE; ESTHER VAZQUEZ

Advanced Science

John Wiley and Sons Inc

Año: 2024

Developing time-sustained drug delivery systems is a main goal in innovativemedicines. Inspired by the architecture of secretory granules from themammalian endocrine system it has generated non-toxic microscale amyloidmaterials through the coordination between divalent metals andpoly-histidine stretches. Like their natural counterparts that keep thefunctionalities of the assembled protein, those synthetic structures releasebiologically active proteins during a slow self-disintegration process occurringin vitro and upon in vivo administration. Being these granules formed by asingle pure protein species and therefore, chemically homogenous, they actas highly promising time-sustained drug delivery systems. Despite theirenormous clinical potential, the nature of the clustering process and thequality of the released protein have been so far neglected issues. By usingdiverse polypeptide species and their protein-only oligomeric nanoscaleversions as convenient models, a conformational rearrangement and astabilization of the building blocks during their transit through the secretorygranules, being the released material structurally distinguishable from theoriginal source is proved here. This fact indicates a dynamic nature ofsecretory amyloids that act as conformational arrangers rather than as plain,inert protein-recruiting/protein-releasing granular depots.