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Commun Biol ; 4(1): 62, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33437023

RESUMEN

Recent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP and identified four different small molecule ligands for this conformer, all capable of selectively lowering the load of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Enfermedades por Prión/tratamiento farmacológico , Proteínas Priónicas/química , Proteínas Priónicas/metabolismo , Pliegue de Proteína , Animales , Sitios de Unión , Simulación por Computador , Retículo Endoplásmico/metabolismo , Fibroblastos , Células HEK293 , Humanos , Ligandos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Procesamiento Proteico-Postraduccional , Reproducibilidad de los Resultados
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