Pharmacological chaperones: a new twist on receptor folding

doi:10.1016/S0165-6147(00)01575-3

Trends in Pharmacological Sciences

Volume 21, Issue 12, 1 December 2000, Pages 466-469

https://doi.org/10.1016/S0165-6147(00)01575-3 Get rights and content

Abstract

Protein misfolding is at the root of several genetic human diseases. These diseases do not stem from mutations within the active domain of the proteins, but from mutations that disrupt their three-dimensional conformation, which leads to their intracellular retention by the quality control apparatus of the cell. Facilitating the escape of the mutant proteins from the quality control system by lowering the temperature of the cells or by adding chemicals that assist folding (chemical chaperones) can result in proteins that are fully functional despite their mutation. The discovery that ligands with pharmacological selectivity (pharmacological chaperones) can rescue the proper targeting and function of misfolded proteins, including receptors, might help to develop new treatments for ‘conformational diseases’.

Section snippets

Protein misfolding and chemical chaperones

Probably the best known example of protein misfolding that is responsible for a disease is the ΔF508 mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which causes cystic fibrosis. The ΔF508 allele of CFTR has been confirmed as a trafficking mutation that blocks the maturation of the protein in the ER and targets it for premature proteolysis ⁶. However, if the ΔF508 protein is redirected to the cell surface, cAMP-mediated transport can be restored.

Pharmacological chaperones

Taking the concept of chemical chaperones a step further, Loo and Clarke have functionally characterized artificial mutations of the multidrug resistance 1 gene (ABCB1), which codes for P-glycoprotein 1, an energy-dependent transporter at the plasma membrane that interacts with a wide variety of cytotoxic agents ¹⁷. The P-glycoprotein 1 mutants generated were retained in the ER as core-glycosylated biosynthetic intermediates. Given that chemical agents such as glycerol can correct protein

Concluding remarks

As the molecular mechanisms of a growing number of genetically inherited diseases are uncovered, it is increasingly appreciated that errors in folding and cellular trafficking are more frequent than anticipated ²⁵. Thus, the development of strategies aimed at promoting proper folding and maturation of mutant proteins could provide new therapies for a wide spectrum of diseases. The observation that small cell-permeable molecules can act as either chemical chaperones or pharmacological

References (25)

H. Sawano
Efficient in vitro folding of the three-disulfide derivatives of hen lysozyme in the presence of glycerol
FEBS Lett.
(1992)
S. Sato
Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation
J. Biol. Chem.
(1996)
R.W. Carrell et al.
Conformational disease
Lancet
(1997)
T.W. Loo et al.
Correction of defective protein kinesis of human P-glycoprotein mutants by substrates and modulars
J. Biol. Chem.
(1997)
L. Ellgaard
Setting the standards: quality control in the secretory pathway
Science
(1999)
P.S. Kim et al.
Endocrinopathies in the family of endoplasmic reticulum (ER) storage diseases: disorders of protein trafficking and the role of ER molecular chaperones
Endocr. Rev.
(1998)
K. Gekko et al.
Mechanisms of protein stabilization by glycerol: preferential hydration in glycerol–water mixtures
Biochemistry
(1981)
M.L. Shelanski
Microtubule assembly in the absence of added nucleotides
Proc. Natl. Acad. Sci. U.S.A.
(1973)
R.R. Kopito
Biosynthesis and degradation of the CFTR
Physiol. Rev.
(1999)
B-S. Kerem
Identification of the cystic fibrosis gene: genetic analysis
Science
(1989)

W. Dalemans

Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation

Nature

(1991)

M.L. Drumm

Chloride conductance expressed by DF508 and other mutant CFTRs in Xenopus oocytes

Science

(1991)

Cited by (215)

Structures of the arginine-vasopressin and oxytocin receptor signaling complexes
2023, Vitamins and Hormones
Arginine-vasopressin (AVP) and oxytocin (OT) are neurohypophysial hormones which share a high sequence and structure homology. These are two cyclic C-terminally amidated nonapeptides with different residues at position 3 and 8. In mammals, AVP and OT exert their multiple biological functions through a specific G protein-coupled receptor family: four receptors are identified, the V1a, V1b, V2 receptors (V1aR, V1bR and V2R) and the OT receptor (OTR). The chemical structure of AVP and OT was elucidated in the early 1950s. Thanks to X-ray crystallography and cryo-electron microscopy, it took however 70 additional years to determine the three-dimensional structures of the OTR and the V2R in complex with their natural agonist ligands and with different signaling partners, G proteins and β-arrestins. Today, the comparison of the different AVP/OT receptor structures gives structural insights into their orthosteric ligand binding pocket, their molecular mechanisms of activation, and their interfaces with canonical Gs, Gq and β-arrestin proteins. It also paves the way to future rational drug design and therapeutic compound development. Indeed, agonist, antagonist, biased agonist, or pharmacological chaperone analogues of AVP and OT are promising candidates to regulate different physiological functions and treat several pathologies.
Vasopressin Type 2 Receptor Agonists and Antagonists
2022, Comprehensive Pharmacology
Regulation of water homeostasis is of vital importance for all terrestrial organisms. In most mammals, the maintenance of water balance is strictly dependent on water excretion in the kidney, which is under the control of the antidiuretic hormone arginine vasopressin (AVP). In the kidney, AVP binds to the vasopressin type 2 receptor (V2R). The alteration of water balance and consequent disorders are closely correlated to the fine regulation of the vasopressin-aquaporin 2 (AQP2) axis in the last tract of the renal tubule, the collecting duct.
Over the last 20 years and currently, the vasopressin—AQP2 axis, via the V2R bridge, was been and is still today the hottest therapeutic target investigated for the treatment of water balance disorders. Therefore, in the last years, significant progress has been made in the discovery and development of vasopressin type 2 receptor (V2R) agonists and antagonists.
In this chapter the recent insights on V2R agonists, antagonists and biased agonists are reported. In addition, new approaches and recent advances for the treatment of water balance disorders are discussed.
Dynamics of prion proliferation under combined treatment of pharmacological chaperones and interferons
2021, Journal of Theoretical Biology
Prions are proteins that cause fatal neurodegenerative diseases. The misfolded conformation adopted by prions can be transmitted to other normally folded proteins. Therapeutics to stop prion proliferation have been studied experimentally; however, it is not clear how the combination of different types of treatments can decrease the growth rate of prions in the brain. In this article, we combine the implementation of pharmacological chaperones and interferons to develop a novel model using a non-linear system of ordinary differential equations and study the quantitative effects of these two treatments on the growth rate of prions. This study aims to identify how the two treatments affect prion proliferation, both individually and in tandem. We analyze the model, and qualitative global results on the disease-free and disease equilibria are proved analytically. Numerical simulations, using parameter values from in vivo experiments that provide a pharmaceutically important demonstration of the effects of these two treatments, are presented here. This mathematical model can be used to identify and optimize the best combination of the treatments within their safe ranges.
Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, ageing, and diseases
2021, Acta Pharmaceutica Sinica B
Cells have different sets of molecules for performing an array of physiological functions. Nucleic acids have stored and carried the information throughout evolution, whereas proteins have been attributed to performing most of the cellular functions. To perform these functions, proteins need to have a unique conformation and a definite lifespan. These attributes are achieved by a highly coordinated protein quality control (PQC) system comprising chaperones to fold the proteins in a proper three-dimensional structure, ubiquitin-proteasome system for selective degradation of proteins, and autophagy for bulk clearance of cell debris. Many kinds of stresses and perturbations may lead to the weakening of these protective cellular machinery, leading to the unfolding and aggregation of cellular proteins and the occurrence of numerous pathological conditions. However, modulating the expression and functional efficiency of molecular chaperones, E3 ubiquitin ligases, and autophagic proteins may diminish cellular proteotoxic load and mitigate various pathological effects. Natural medicine and small molecule-based therapies have been well-documented for their effectiveness in modulating these pathways and reestablishing the lost proteostasis inside the cells to combat disease conditions. The present article summarizes various similar reports and highlights the importance of the molecules obtained from natural sources in disease therapeutics.
Intracellular Trafficking of G Protein-Coupled Receptors to the Cell Surface Plasma Membrane in Health and Disease
2021, Cellular Endocrinology in Health and Disease, Second Edition
Proteins are synthesized in the endoplasmic reticulum (ER) of the cell, where a strict quality control system (QCS) guards against aberrant protein structures and non-productive protein aggregation. The ER QCS checks for adequate folding and structural integrity of nascent proteins so that only properly folded and assembled secretory and membrane proteins may reach their final destination within the cell. For this task, the ER QCS relies on different strategies, including the action of members of major molecular chaperone families. As any other protein, G protein-coupled receptors (GPCRs) are subjected to structural and conformational scrutiny at the ER before processing and trafficking to the plasma membrane. Mutations in these integral membrane proteins may provoke misfolding, retention, and eventually degradation of the defective protein receptor, leading to disease. In this chapter, we review the mechanisms governing upward and downward trafficking of this class of membrane receptors, including interactions with molecular chaperones and scaffold molecules, and the role of some structural requirements for proper intracellular trafficking. We also exemplify how misfolding may lead to disease and describe different strategies to rescue the function of misfolded GPCRs in vitro and in vivo.
Differential scanning fluorimetry in the screening and validation of pharmacological chaperones for soluble and membrane proteins
2020, Protein Homeostasis Diseases: Mechanisms and Novel Therapies
Pharmacological chaperoning by small compounds that stabilize and increase the steady-state intracellular levels of functional conformations of disease-causing protein variants is a relatively novel therapeutic approach. Customary screens are based on the monitoring of protein stabilization, where differential scanning fluorimetry is a method that has been successfully used to discover initial hits, notably for soluble cytoplasmic proteins. High-throughput biophysical screens of recombinantly expressed integral membrane proteins solubilized in detergent are less common. We here present DSF-based screens for either soluble or membrane proteins, using SYPRO Orange and N-[4-(7-diethylamino-4-methyl-3-coumarinyl)phenyl]maleimide (CPM) as the fluorescent dyes, respectively. Furthermore, concentration-dependent DSF is also an adequate method for first validation of initial hits for further characterization and initiation of hit-to-lead chemistry programs for the development of drug candidates to treat misfolding genetic diseases.

View all citing articles on Scopus

View full text

Trends in Pharmacological Sciences

ViewpointPharmacological chaperones: a new twist on receptor folding

Abstract

Section snippets

Protein misfolding and chemical chaperones

Pharmacological chaperones

Concluding remarks

FEBS Lett.

J. Biol. Chem.

Lancet

J. Biol. Chem.

Setting the standards: quality control in the secretory pathway

Science

Endocrinopathies in the family of endoplasmic reticulum (ER) storage diseases: disorders of protein trafficking and the role of ER molecular chaperones

Endocr. Rev.

Mechanisms of protein stabilization by glycerol: preferential hydration in glycerol–water mixtures

Biochemistry

Microtubule assembly in the absence of added nucleotides

Proc. Natl. Acad. Sci. U.S.A.

Biosynthesis and degradation of the CFTR

Physiol. Rev.

Identification of the cystic fibrosis gene: genetic analysis

Science

Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation

Nature

Chloride conductance expressed by DF508 and other mutant CFTRs in Xenopus oocytes

Science

Viewpoint
Pharmacological chaperones: a new twist on receptor folding