Pharmacoperones as Novel Therapeutics for Diverse Protein Conformational Diseases

Tao, Ya-Xiong; Conn, P. Michael

doi:10.1152/physrev.00029.2016

Cited by 80 publications

(63 citation statements)

References 413 publications

(420 reference statements)

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“…It has been observed that PCs can increase the enzyme activity of the mutant proteins in a mutation-dependent manner, which may be sufficient to ameliorate most disease symptoms [49,50]. In addition, it has been observed that these drugs can enhance the stability of recombinant lysosomal enzymes, suggesting that co-administration of a PC and recombinant enzyme may increase the efficacy of the ERT [3,51]. Here, we will highlight some of the studies that have identified and characterized PCs for LSDs.…”

Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 99%

“…These proteins, also called molecular chaperones, act on proteins that reach the endoplasmic reticulum (ER) and on some cytosolic proteins, aiding in the proper folding of unfolded and misfolded proteins. In this sense, molecular chaperones reduce the amount of proteins that are targeted for degradation by decreasing their aggregation and proteasome targeting [3]. The ER environment is very different from that of the cytosol since it has an oxidizing nature that helps the disulfide bond formation and it also has a mM concentration of Ca 2+ , which acts as a folding buffer [4].…”

Section: Introductionmentioning

confidence: 99%

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Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Diaz

Castillo

Rodríguez-López

et al. 2019

IJMS

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The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. It this sense, it has been proposed that the use of small molecules, called pharmacological chaperones (PCs), can restore the folding, trafficking, and biological activity of mutated enzymes. PCs have the advantages of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity than enzyme replacement therapy. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

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Section: Use Of Pharmacological Chaperones In Lsdsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Diaz

Castillo

Rodríguez-López

et al. 2019

IJMS

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“…Pharmacological chaperones have ceased to be a niche category and have entered the clinical practice for some rare diseases caused primarily by protein instability. Many reviews exist to cover this subject with different points of view (a few examples [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]). We wanted to contribute by providing the readers with a list of research papers organized per disease that covers the years from 2000 to 2018.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

Liguori

Monticelli

Allocca

et al. 2020

IJMS

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The term “pharmacological chaperone” was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.

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“…For human diseases caused by proteostasis impairment, it is essential to identify or develop novel biological and chemical therapeutics aiming at optimizing protein conformation and enhancing proteostasis capacity (130,177,178). For example, the Hsp90 inhibitor 17-AAG may serve as a potential pharmacological chaperone (pharmacochaperone) for modifying impaired proteostasis network of neurodegenerative diseases such as motor neuron degeneration and spinocerebellar ataxia (131, 179,180).…”

Section: Clinical Significancementioning

confidence: 99%

Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita

Jeng¹,

You

et al. 2020

Front. Neurol.

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The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this Jeng et al.ClC-1 Proteostasis and Myotonia chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.

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Pharmacoperones as Novel Therapeutics for Diverse Protein Conformational Diseases

Cited by 80 publications

References 413 publications

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita

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