Pharmacological chaperone approaches for rescuing GPCR mutants: Current state, challenges, and screening strategies

Beerepoot, Pieter; Nazari, Reza; Salahpour, Ali

doi:10.1016/j.phrs.2016.12.036

Cited by 29 publications

(19 citation statements)

References 99 publications

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“…Both V2R mutants and wild-type V2R are constitutively misfolded and degraded in the ER. Protein folding efficiency of G-protein coupled receptors, including V2R, is only <50% 35 . Tolvaptan may directly bind to misfolded wild-type V2R in the ER and subsequently modulate PERK phosphorylation without activation of the ER stress transducer, IRE-1 (Figs 2e, 6).…”

Section: Discussionmentioning

confidence: 99%

Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation

Fujiki

Ando

Murakami

et al. 2019

Sci Rep

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Tolvaptan, a vasopressin type 2 receptor antagonist initially developed to increase free-water diuresis, has been approved for the treatment of autosomal dominant polycystic kidney disease in multiple countries. Furthermore, tolvaptan has been shown to improve the renal functions in rodent models of chronic kidney disease (CKD); however, the underlying molecular mechanisms remain unknown. CKD is characterized by increased levels of oxidative stress, and an antioxidant transcription factor—nuclear factor erythroid 2-related factor 2 (Nrf2)—has been gaining attention as a therapeutic target. Therefore, we investigated the effects of tolvaptan and a well-known Nrf2 activator, bardoxolone methyl (BARD) on Nrf2. To determine the role of tolvaptan, we used a renal cortical collecting duct (mpkCCD) cell line and mouse kidneys. Tolvaptan activated Nrf2 and increased mRNA and protein expression of antioxidant enzyme heme oxygenase-1 (HO-1) in mpkCCD cells and the outer medulla of mouse kidneys. In contrast to BARD, tolvaptan regulated the antioxidant systems via a unique mechanism. Tolvaptan activated the Nrf2/HO-1 antioxidant pathway through phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, tolvaptan and BARD could successfully generate synergistic activating effects on Nrf2/HO-1 antioxidant pathway, suggesting that this combination therapy can contribute to the treatment of CKD.

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Section: Discussionmentioning

confidence: 99%

Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation

Fujiki

Ando

Murakami

et al. 2019

Sci Rep

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“…Beyond the ability of endogenous ligands, such as cofactors, to promote the native folding of enzymes, the rapidly expanding field of pharmacological chaperones provides convincing proof-of-concept evidence that the folding of receptors can be facilitated by target-selective exogenous ligands. Pharmacological chaperones are small molecules (drugs) that bind to nascent target proteins, within the ER lumen in the case of integral membrane proteins, and aid in the biogenesis of their target proteins (Leidenheimer and Ryder, 2014 ; Beerepoot et al, 2017 ). These target proteins include a broad array of receptors, ion channels, transporters, and enzymes.…”

Section: Proof-of-concept: From Enzyme Cofactors To Pharmacological Cmentioning

confidence: 99%

“…Of relevance to the present paper, a number of neurotransmitter receptors have been observed to undergo pharmacological chaperoning including ligand-gated ion channels, in both the Cys loop and bacterial superfamilies, and G protein-coupled receptors. While early studies of pharmacological chaperones focused on the ability of pharmacological chaperones to rescue the biogenesis and surface expression of ER-retained, disease-associated receptor mutants (Beerepoot et al, 2017 ), it subsequently became clear that the biogenesis of recombinant wild type receptors, such as the δ-opioid, dopamine D4, β1-adrenergic, serotonin 5-HT2, adenosine A2, nicotinic acetylcholine, and GABA A receptors was also facilitated by pharmacological chaperones (Petaja-Repo et al, 2000 , 2002 ; Janovick et al, 2002 ; Kuryatov et al, 2005 ; Sallette et al, 2005 ; Corringer et al, 2006 ; Van Craenenbroeck et al, 2006 ; Chen and Liu-Chen, 2009 ; Kobayashi et al, 2009 ; Lester et al, 2009 ; Eshaq et al, 2010 ; Srinivasan et al, 2011 ; Kusek et al, 2015 ). Thus, pharmacological chaperoning provides proof-of-concept that small, receptor-specific ligands can drive neurotransmitter receptor biogenesis and supports the possibility that neurotransmitters themselves, if present in the ER lumen, may regulate the biogenesis of their cognate receptors.…”

Section: Proof-of-concept: From Enzyme Cofactors To Pharmacological Cmentioning

confidence: 99%

Cognate Ligand Chaperoning: a Novel Mechanism for the Post-translational Regulation of Neurotransmitter Receptor Biogenesis

Leidenheimer

2017

Front. Cell. Neurosci.

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The functional unit for inter-neuronal communication in the central nervous system is the neuronal synapse. The number of postsynaptic neurotransmitter receptors at the cell surface is an important determinant of synaptic efficacy and plasticity. A diverse array of post-translational processes regulate postsynaptic receptor number, including receptor exocytosis, lateral diffusion, surface stabilization, endocytosis, and recycling, thus highlighting the importance of mechanisms that control postsynaptic receptor levels. Another putative post-translational mechanism for regulating receptor surface expression is cognate ligand chaperoning. It has been proposed that neurotransmitters function as cognate ligand chaperones by binding, within the endoplasmic reticulum (ER) lumen, to their nascent neurotransmitter receptors and facilitating receptor biogenesis. Here we discuss proof-of-concept evidence that small molecules can selectively facilitate the biogenesis of their targets and examine the specific evidence in support of cognate ligand chaperoning of neurotransmitter receptor biogenesis.

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“…Moreover, these first-generation pharmacoperones are not limited to the pair “enzyme/competitive inhibitor”. This concept has also been extended to orthosteric ligands for receptors [ 14 ] as well as correctors for transporters, such as CFTR [ 15 ]. Many studies demonstrated the potential of these first-generation PCs to thermodynamically stabilize proper protein folding at rather low concentration.…”

Section: Introductionmentioning

confidence: 99%

“…Since the appearance of the concept of PC [ 12 , 13 ], among hundreds of research articles referencing this therapeutic approach, more than sixty percent deal with enzymopathies [ 6 ]. Many review articles were also published, either focusing on a specific pathology [ 17 , 18 , 20 ], a specific target [ 14 , 21 ] or stressing on a specific point of view [ 22 , 23 ]. We dedicated the present literature survey to non-inhibitory PCs, regarded as the “second-generation pharmacoperones”, and we concentrated our attention on enzymes since they represent the large majority of the PC targets.…”

Section: Introductionmentioning

confidence: 99%

Second-Generation Pharmacological Chaperones: Beyond Inhibitors

et al. 2020

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Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.

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Pharmacological chaperone approaches for rescuing GPCR mutants: Current state, challenges, and screening strategies

Cited by 29 publications

References 99 publications

Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation

Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation

Cognate Ligand Chaperoning: a Novel Mechanism for the Post-translational Regulation of Neurotransmitter Receptor Biogenesis

Second-Generation Pharmacological Chaperones: Beyond Inhibitors

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