Identifying the molecular target sites for CFTR potentiators GLPG1837 and VX-770

Yeh, Han I.; Qiu, Liming; Saito, Yoshiro; Conrath, Katja; Zou, Xiaoqin; Hwang, Tzyh Chang

doi:10.1085/jgp.201912360

Cited by 62 publications

(70 citation statements)

References 75 publications

(134 reference statements)

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“…Interestingly, the simultaneous administration of ABBV-974 or ABBV-2451 with ivacaftor did not further enhance CFTR function, indicating that these molecules may act by the same mechanism of action (Yeh et al, 2017;Van der Plas et al, 2018). In fact, recent reports demonstrated that ABBV-974 and ivacaftor share a common binding site at the interface between the two TMDs near the kink of helix 8 (Liu F. et al, 2019;Yeh et al, 2019) (Figure 7). In a phase IIa trial, patients were subjected to a one-week ivacaftor washout before receiving three consecutive and increasing doses of ABBV-974.…”

Section: Potentiators: Restoring the Channel Gating And Conductancementioning

confidence: 93%

“…Some initial reports indicated that ivacaftor might bind to a region of amino acids at the NBD1/2 interface and the coupling helix of intracellular loop 1 (Veit et al, 2014) and/or the 'ball-and-socket' joint close to intracellular loop 4 (Byrnes et al, 2018). More recent studies provided direct evidence of the binding site of ivacaftor at the interface between TMDs by using electron cryomicroscopy and electrophysiological assays (Liu F. et al, 2019;Yeh et al, 2019). As chemical interactions are dynamic and the protein undergoes multiple conformational changes during channel opening and closure, some binding sites might also differ depending on the protein conformational state.…”

Section: Potentiators: Restoring the Channel Gating And Conductancementioning

confidence: 99%

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CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

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Section: Potentiators: Restoring the Channel Gating And Conductancementioning

confidence: 93%

Section: Potentiators: Restoring the Channel Gating And Conductancementioning

confidence: 99%

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

2020

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“…1B, left). However, the application of 20 µM GLPG1837, a CFTR potentiator, which shares the same mechanism of action and binding sites as the FDA-approved drug Ivacaftor (Yeh et al 2017(Yeh et al , 2019a, greatly increased the current by 29.3 ± 3.4-fold (N = 5), indicating that the P o of the channel recorded was extremely low; as the maximal P o of an ion channel is 1, the P o of W1282X-CFTR must be <0.034 or 1/29.3, vs. ß0.4 for WT-CFTR (Yeh et al 2015).…”

Section: Chloride Currents Carried By a Mixture Of C-terminus Truncatmentioning

confidence: 99%

“…We next investigated the kinetic properties and the responses to pharmacological reagents of E60X-and G542X-CFTR. Specifically, we tested the effects of the high-affinity ATP analogue N(6)-(2-phenylethyl)-2deoxy-ATP (P-dATP), which works on the NBDs (Miki et al 2010), and the CFTR potentiator GLPG1837, which acts on CFTR's TMDs (Yeh et al 2017(Yeh et al , 2019a, on the kinetic parameters of endogenous read-through (preincubated with 3 µM VX-809) or drug-facilitated read-through (preincubated with 150 µM G418) proteins of E60X-and G542X-CFTR. Figure 9 shows representative single-channel recordings of E60X-CFTR from cells preincubated with VX-809 (black trace) or G418 (blue trace) with their respective responses to P-dATP and GPLG1837.…”

Section: Figure 7 Whole-cell Recordings Of E60x-and G542x-cftr Reveamentioning

confidence: 99%

Positional effects of premature termination codons on the biochemical and biophysical properties of CFTR

Yeh

Hwang

2019

The Journal of Physiology

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Key points Biochemical and biophysical characterizations of three nonsense mutations of cystic fibrosis transmembrane conductance regulator (CFTR) associated with a severe form of cystic fibrosis (CF) reveal the importance and heterogenous effects of the position of the premature termination codon (PTC) on the CFTR protein function. Electrophysiological studies of W1282X‐CFTR, whose PTC is closer to the C‐terminus of CFTR, suggest the presence of both C‐terminus truncated CFTR proteins that are poorly functional and read‐through, full‐length products. For G542X‐ and E60X‐CFTR, the only mechanism capable of generating functional proteins is the read‐through, but the outcome of read‐through products is highly variable depending on the interplay between the missense mutation caused by the read‐through and the structural context of the protein. Pharmacological studies of these three PTCs with various CFTR modulators suggest position‐dependent therapeutic strategies for these disease‐inflicting mutations. Abstract About one‐third of genetic diseases and cancers are caused by the introduction of premature termination codons (PTCs). In theory, the location of the PTC in a gene determines the alternative mechanisms of translation, including premature cessation or reinitiation of translation, and read‐through, resulting in differential effects on protein integrity. In this study, we used CFTR as a model system to investigate the positional effect of the PTC because of its well‐understood structure‐function relationship and pathophysiology. The characterization of three PTC mutations, E60X‐, G542X‐ and W1282X‐CFTR revealed heterogenous effects of these PTCs on CFTR function. The W1282X mutation results in both C‐terminus truncated and read‐through proteins that are partially or fully functional. In contrast, only the read‐through protein is functional with E60X‐ and G542X‐CFTR, although abundant N‐terminus truncated proteins due to reinitiation of translation were detected in E60X‐CFTR. Single‐channel studies of the read‐through proteins of E60X‐ and G542X‐CFTR demonstrated that both mutations have a single‐channel amplitude similar to wild type (WT), and good responses to high‐affinity ATP analogues, suggesting intact ion permeation pathways and nucleotide binding domains (NBDs), albeit with reduced open probability (Po). The comparison of the Po of these mutations with the proposed missense mutations revealed potential identities of the read‐through products. Importantly, a majority of the functional protein studied responds to CFTR modulators like GLPG1837 and Lumacaftor. These results not only expand current understanding of the molecular (patho)physiology of CFTR, but also infer therapeutic strategies for different PTC mutations at large.

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“…Among the computational models listed above, only a few have been used to better characterize the binding mode of known F508del-CFTR-rescuing drugs, to virtually screen libraries of molecules aimed at the identification of new putative F508del-CFTR-binding compounds or to design new CFTR-targeted drugs [48,49]. On the contrary, a huge amount of computational studies has been developed in the attempt of clarifying at a molecular level the mechanism of action of F508del-CFTR-ligands, using several NBDs RX data [23,[50][51][52] or the more recent cryo EM structures [53].…”

Section: Cftr Computational Modelsmentioning

confidence: 99%

Recent Strategic Advances in CFTR Drug Discovery: An Overview

Rusnati

D’Ursi

Pedemonte

et al. 2020

IJMS

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Cystic fibrosis transmembrane conductance regulator (CFTR)-rescuing drugs have already transformed cystic fibrosis (CF) from a fatal disease to a treatable chronic condition. However, new-generation drugs able to bind CFTR with higher specificity/affinity and to exert stronger therapeutic benefits and fewer side effects are still awaited. Computational methods and biosensors have become indispensable tools in the process of drug discovery for many important human pathologies. Instead, they have been used only piecemeal in CF so far, calling for their appropriate integration with well-tried CF biochemical and cell-based models to speed up the discovery of new CFTR-rescuing drugs. This review will give an overview of the available structures and computational models of CFTR and of the biosensors, biochemical and cell-based assays already used in CF-oriented studies. It will also give the reader some insights about how to integrate these tools as to improve the efficiency of the drug discovery process targeted to CFTR.

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Identifying the molecular target sites for CFTR potentiators GLPG1837 and VX-770

Cited by 62 publications

References 75 publications

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Positional effects of premature termination codons on the biochemical and biophysical properties of CFTR

Recent Strategic Advances in CFTR Drug Discovery: An Overview

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