Role of misfolding in rare enzymatic deficits and use of pharmacological chaperones as therapeutic approach.
Front Biosci (Landmark Ed)
; 26(12): 1627-1642, 2021 12 30.
Article
en En
| MEDLINE
| ID: mdl-34994177
ABSTRACT
Cells have evolved sophisticated molecular control systems to maximize the efficiency of the folding process. However, any subtle alteration of the environment or the protein can lead to misfolding or affect the conformational plasticity of the native states. It has been widely demonstrated that misfolding and/or conformational instability are the underlying mechanisms of several rare disorders caused by enzymatic deficits. In fact, disease-causing mutations often lead to the substitution of amino acids that are crucial for the achievement of a folded conformation, or play a role on the equilibrium between native-state conformers. One of the promising approaches to treat conformational disorders is the use of pharmacological chaperones (PCs), small molecules that specifically bind a target protein and stabilize a functional fold, thus increasing the amount of functionally active enzyme. Molecules acting as PCs are usually coenzymes, substrate analogues behaving as competitive inhibitors, or allosteric modulators. In this review, the general features of PCs are described, along with three examples of diseases (Gaucher disease, Phenylketonuria, and Primary Hyperoxaluria) in which this approach is currently under study at preclinical and/or clinical level.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Deficiencias en la Proteostasis
/
Enfermedad de Gaucher
Límite:
Humans
Idioma:
En
Revista:
Front Biosci (Landmark Ed)
Año:
2021
Tipo del documento:
Article
País de afiliación:
Italia