IMR Press / FBL / Volume 26 / Issue 12 / DOI: 10.52586/5056
Open Access Review
Role of misfolding in rare enzymatic deficits and use of pharmacological chaperones as therapeutic approach
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1 Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
*Correspondence: (Barbara Cellini)
Academic Editor: Josef Jampilek
Front. Biosci. (Landmark Ed) 2021, 26(12), 1627–1642;
Submitted: 28 August 2021 | Revised: 28 October 2021 | Accepted: 5 November 2021 | Published: 30 December 2021
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.

Parmacological chaperones
Gaucher disease
Primary hyperoxaluria
Fig. 1.
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