Nanomaterials inspirats en prions i les seves aplicacions biomèdiques
- Autores: Weiqiang Wang
- Directores de la Tesis: Susanna Navarro Cantero (dir. tes.), Salvador Ventura Zamora (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2020
- Idioma: catalán
- ISBN: 9788449097577
- Tribunal Calificador de la Tesis: Xavier Fernández Busquets (presid.), David Reverter Cendrós (secret.), Anna Villar Piqué (voc.)
- Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Amyloids display a highly ordered fibrillar structure. Many of these assemblies appear associated with human disease. However, the controllable, stable, tunable, and robust nature of amyloid fibrils can be exploited to build up remarkable nanomaterials with a wide range of applications.
Functional prions constitute a particular class of amyloids. These transmissible proteins exhibit a modular architecture, with a disordered prion domain responsible for the assembly and one or more globular domains that account for the activity. Importantly, the original globular protein can be replaced with any protein of interest, without compromising the fibrillation potential. These genetic fusions form fibrils in which the globular domain remains folded, rendering functional nanostructures. However, in many cases, steric hindrance restricts the activity of these fibrils. This limitation can be solved by dissecting prion domains into shorter sequences that keep their self-assembling properties while allowing better access to the protein in the fibrillar state.
In this PhD thesis, we exploited the “soft amyloid core (SAC)” of the Sup35p yeast prion as a modular self-assembling unit, which recapitulates the aggregation propensity of the complete prion domain. We fused the SAC to different globular proteins of interest differing in conformation and sizes, building up a general and straightforward genetic approach to generate nanofibrils endowed with desired functionalities. Computational modeling allowed us to gain insights into the relationship between the size of the globular domains and the length of the linker that connects them to the SAC, providing the basis for the design of nanomaterials with different mesoscopic properties, either nanofibrils or nanoparticles. On this basis, we designed and produced, for the first time, highly active, non-toxic, spherical amyloid nanoparticles of defined size and engineered bifunctional nanostructures with application in targeted drug delivery. The lessons learned in these exercises resulted in the construction of a bispecific antibody-like nanofibril, showing potential in immunotherapy. In summary, the prion-like functional nanomaterials described here take profit of the genetic fusion approach to render a novel set of structures with application in biomedicine and biotechnology.
