Therapeutic Rescue of Misfolded/Mistrafficked Mutants

Smithson, David C.; Conn, P. Michael

doi:10.1016/b978-0-12-391862-8.00001-6

Cited by 18 publications

(5 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As in vivo application moves to the forefront, practical considerations, such as the need for potentiators (cystic fibrosis) or pulsatile administration (hypogonadotropic hypogonadism, nephrogenic diabetes insipidus), become evident and optimization of treatment approach will be necessary to realize the full potential of PCs. The identification of efficacious PCs should be greatly accelerated by the use of cell-based high-throughput screening [156–159]. Largely uninvestigated, pharmacological chaperoning activity of currently used therapeutic agents may partially account for their beneficial clinical effects, and in some cases may underlie drug toxicity.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological chaperoning: A primer on mechanism and pharmacology

Leidenheimer

Ryder

2014

Pharmacological Research

View full text Add to dashboard Cite

Approximately forty percent of diseases are attributable to protein misfolding, including those for which genetic mutation produces misfolding mutants. Intriguingly, many of these mutants are not terminally misfolded since native-like folding, and subsequent trafficking to functional locations, can be induced by target-specific, small molecules variably termed pharmacological chaperones, pharmacoperones, or pharmacochaperones (PCs). PC targets include enzymes, receptors, transporters, and ion channels, revealing the breadth of proteins that can be engaged by ligand-assisted folding. The purpose of this review is to provide an integrated primer of the diverse mechanisms and pharmacology of PCs. In this regard, we examine the structural mechanisms that underlie PC rescue of misfolding mutants, including the ability of PCs to act as surrogates for defective intramolecular interactions and, at the intermolecular level, overcome oligomerization deficiencies and dominant negative effects, as well as influence the subunit stoichiometry of heteropentameric receptors. Not surprisingly, PC-mediated structural correction of misfolding mutants normalizes interactions with molecular chaperones that participate in protein quality control and forward-trafficking. A variety of small molecules have proven to be efficacious PCs and the advantages and disadvantages of employing orthostatic antagonists, active-site inhibitors, orthostatic agonists, and allosteric modulator PCs is considered. Also examined is the possibility that several therapeutic agents may have unrecognized activity as PCs, and this chaperoning activity may mediate/contribute to therapeutic action and/or account for adverse effects. Lastly, we explore evidence that pharmacological chaperoning exploits intrinsic ligand-assisted folding mechanisms. Given the widespread applicability of PC rescue of mutants associated with protein folding disorders, both in vitro and in vivo, the therapeutic potential of PCs is vast. This is most evident in the treatment of lysosomal storage disorders, cystic fibrosis, and nephrogenic diabetes insipidus, for which proof of principle in humans has been demonstrated.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacological chaperoning: A primer on mechanism and pharmacology

Leidenheimer

Ryder

2014

Pharmacological Research

View full text Add to dashboard Cite

show abstract

“…616,619,775,792–796 Small molecule screening has identified additional molecules that act as PCs, though it is unclear how these compounds influence the activation state of V2R. 799 Only one such PC has been evaluated in short-term NDI clinical trials to date. 616 A 24 h administration of SR49059 in NDI patients bearing V2R mutations significantly decreased patient urine volume, increased urine osmolarity, and increased water intake into the bloodstream, all suggesting a significant clinical benefit in these patients.…”

Section: Small Molecule Manipulation Of Membrane Protein Foldingmentioning

confidence: 99%

“…An ultrahigh-throughput cellular assay that leverages changes in cellular cAMP, a downstream reporter of G α s signaling, has been developed to identify PCs for destabilized V2R variants. 797–799 This assay was employed using HeLa cells stably expressing L83Q V2R under the control of a tetracycline-controlled transactivator. The use of an inducible expression system provides a convenient means to detect false positives.…”

Section: Small Molecule Manipulation Of Membrane Protein Foldingmentioning

confidence: 99%

Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis

et al. 2019

View full text Add to dashboard Cite

Advances over the past 25 years have revealed much about how the structural properties of membranes and associated proteins are linked to the thermodynamics and kinetics of membrane protein (MP) folding. At the same time biochemical progress has outlined how cellular proteostasis networks mediate MP folding and manage misfolding in the cell. When combined with results from genomic sequencing, these studies have established paradigms for how MP folding and misfolding are linked to the molecular etiologies of a variety of diseases. This emerging framework has paved the way for the development of a new class of small molecule “pharmacological chaperones” that bind to and stabilize misfolded MP variants, some of which are now in clinical use. In this review, we comprehensively outline current perspectives on the folding and misfolding of integral MPs as well as the mechanisms of cellular MP quality control. Based on these perspectives, we highlight new opportunities for innovations that bridge our molecular understanding of the energetics of MP folding with the nuanced complexity of biological systems. Given the many linkages between MP misfolding and human disease, we also examine some of the exciting opportunities to leverage these advances to address emerging challenges in the development of therapeutics and precision medicine.

show abstract

“…In fact, more than 30 disorders are associated with mutations in GPCRs, which make these proteins a target for drug development (Lagerstrom and Schioth, 2008; Overington et al, 2006; Schlyer and Horuk, 2006). Although the majority of pharmacoperones identified that rescue misfolded GPCRs are mainly antagonists of the natural ligand detected from “hits” in screens designed to detect antagonists or agonists, new, fully automated high-throughput assays for identification of “pure” pharmacoperone drugs of mutant GPCRs have been recently described (Smithson et al, 2013). These approaches allow identification of structures missed in screens designed to select only agonists or antagonists, and thus offer the advantage of identifying new classes of drugs which are specific and rescue active, but do not have inherent modulatory activity (stimulatory or inhibitory).…”

Section: Discussionmentioning

confidence: 99%

Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function

Ulloa‐Aguirre

Zariñán²,

Dias

et al. 2014

Molecular and Cellular Endocrinology

Self Cite

View full text Add to dashboard Cite

G protein coupled receptors (GPCRs) are a large superfamily of integral cell surface plasma membrane proteins that play key roles in transducing extracellular signals, including sensory stimuli, hormones, neurotransmitters, or paracrine factors into the intracellular environment through the activation of one or more heterotrimeric G proteins. Structural alterations provoked by mutations or variations in the genes coding for GPCRs may lead to misfolding, altered plasma membrane expression of the receptor protein and frequently to disease. A number of GPCRs regulate reproductive function at different levels; these receptors include the gonadotropin-releasing hormone receptor (GnRHR) and the gonadotropin receptors (follicle-stimulating hormone receptor and luteinizing hormone receptor), which regulate the function of the pituitary-gonadal axis. Loss-of-function mutations in these receptors may lead to hypogonadotropic or hypergonadotropic hypogonadism, which encompass a broad spectrum of clinical phenotypes. In this review we describe mutations that provoke misfolding and failure of these receptors to traffick from the endoplasmic reticulum to the plasma membrane. We also discuss some aspects related to the therapeutic potential of some target-specific drugs that selectively bind to and rescue function of misfolded mutant GnRHR and gonadotropin receptors, and that represent potentially valuable strategies to treat diseases caused by inactivating mutations of these receptors.

show abstract

Therapeutic Rescue of Misfolded/Mistrafficked Mutants

Cited by 18 publications

References 40 publications

Pharmacological chaperoning: A primer on mechanism and pharmacology

Pharmacological chaperoning: A primer on mechanism and pharmacology

Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis

Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function

Contact Info

Product

Resources

About