Open Access

Role of misfolding in rare enzymatic deficits and use of pharmacological chaperones as therapeutic approach

Gioena Pampalone1,Silvia Grottelli1,Leonardo Gatticchi1,Emilia Maria Lombardi1, Ilaria Bellezza1,Barbara Cellini1,*
Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
DOI: 10.52586/5056 Volume 26 Issue 12, pp.1627-1642
Submited: 28 August 2021 Revised: 28 October 2021
Accepted: 05 November 2021 Published: 30 December 2021
*Corresponding Author(s):  
Barbara Cellini
Copyright: © 2021 The author(s). Published by BRI. This is an open access article under the CC BY 4.0 license (

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.

Key words

Misfolding; Parmacological chaperones; Gaucher disease; Phenylketonuria; Primary hyperoxaluria

Share and Cite
Gioena Pampalone, Silvia Grottelli, Leonardo Gatticchi, Emilia Maria Lombardi, Ilaria Bellezza, Barbara Cellini. Role of misfolding in rare enzymatic deficits and use of pharmacological chaperones as therapeutic approach. Frontiers in Bioscience-Landmark. 2021. 26(12); 1627-1642.