Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Bacalhau, Mafalda; Ferreira, F. Castela; Silva, Iris; Buarque, Camilla D.; Amaral, Margarida D.; Lopes‐Pacheco, Miquéias

doi:10.3390/jpm13010102

Cited by 7 publications

(4 citation statements)

References 64 publications

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“…It should be noted that, despite the therapeutic accomplishments of ivacaftor, it only attains a partial restoration of the CFTR gating activity [ 42 , 47 , 66 ]. Accordingly, novel potentiators have been investigated, and their combination with complementary mechanisms (i.e., co-potentiators) has emerged as a strategy to further enhance CFTR gating activity [ 66 , 67 , 68 , 69 , 70 , 71 ].…”

Section: Ivacaftor (Vx-770)mentioning

confidence: 99%

Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor

Ferreira,

Buarque,

Lopes-Pacheco

2024

Molecules

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The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators—small molecules acting on the basic molecular defect in CF—have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA’s) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.

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Section: Ivacaftor (Vx-770)mentioning

confidence: 99%

Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor

Ferreira,

Buarque,

Lopes-Pacheco

2024

Molecules

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“…Similar advantages were observed in younger children in the KIWI study. Since then, ivacaftor has been authorized for a number of CFTR gating and residual function alterations, demonstrating its therapeutic efficacy for a range of age groups and mutations [ 76 ]. LUMA + IVA in PwCF ≥ 12 years homozygous for F508del-CFTR was investigated in two 24-week phase 3 trials, TRAFFIC and TRANSPORT.…”

Section: Monotherapy To Triple Combination Therapy (Eti)mentioning

confidence: 99%

“…Subsequent research in children aged 6 to 11 revealed notable gains in lung function, but not in BMI or CFQ-R ratings; several unfavorable side-effects forced the trial’s termination. Although the effectiveness of the combination therapy is recognized, its usage is restricted due to concerns about drug interactions and safety [ 62 , 76 , 77 , 78 , 79 ].…”

Section: Monotherapy To Triple Combination Therapy (Eti)mentioning

confidence: 99%

Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies

Anwar,

Peng,

Zahid

et al. 2024

ARM

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A common life-threatening hereditary disease, Cystic Fibrosis (CF), affects primarily Caucasian infants. High sweat-salt levels are observed as a result of a single autosomal mutation in chromosome 7 that affects the critical function of the cystic fibrosis transmembrane regulator (CFTR). For establishing tailored treatment strategies, it is important to understand the broad range of CFTR mutations and their impacts on disease pathophysiology. This study thoroughly investigates the six main classes of classification of CFTR mutations based on their functional effects. Each class is distinguished by distinct molecular flaws, such as poor protein synthesis, misfolding, gating defects, conduction defects, and decreased CFTR expression at the apical membrane. Furthermore, this paper focuses on the emerging field of CFTR modulators, which intend to restore CFTR function or mitigate its consequences. These modulators, which are characterized by the mode of action and targeted mutation class, have the potential to provide personalized therapy regimens in CF patients. This review provides valuable insights into the genetic basis of CF pathology, and highlights the potential for precision medicine methods in CF therapy by thoroughly investigating CFTR mutation classification and related modulators.

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“…Critical steps in a translational research pipeline often require a simple cellular model. Among the most prominent examples is the development of small molecule therapies using a simple cell-based in vitro assay for CFTR deficiency to develop therapeutics for cystic fibrosis ( Langron et al, 2017 ; Phuan et al, 2018 ; Bacalhau et al, 2023 ). In addition, haploid cell models offer a powerful tool for genetic screening of phenotypic modifiers, such as suppressors and enhancers.…”

Section: Introductionmentioning

confidence: 99%

Targeting NHE6 gene expression identifies lysosome and neurodevelopmental mechanisms in a haploid in vitro cell model

Wu,

Ma,

Joesch-Cohen

et al. 2023

Biology Open

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Christianson Syndrome (CS) is an X-linked disorder resulting from loss-of-function (LoF) mutations in SLC9A6 encoding the endosomal Na+/H+ exchanger 6 (NHE6). CS presents with developmental delay, seizures, intellectual disability, nonverbal status, postnatal microcephaly, and ataxia. To define transcriptome signatures of NHE6 LoF, we conducted in-depth RNA-sequencing (RNA-seq) analysis on a haploid NHE6 null cell model. CRIPSR/Cas9 genome editing introduced multiple LoF mutations into SLC9A6 in the near haploid human cell line Hap1. Isogenic, paired parental controls were also studied. NHE6 mutant cell lines were confirmed to have intra-endosomal over-acidification as was seen in other NHE6 null cells. RNA-seq analysis was performed by two widely used pipelines: HISAT2-StringTie-DEseq2 and STAR-HTseq-DEseq2. We identified 1056 differentially expressed genes in mutant NHE6 lines, including genes associated with neurodevelopment, synapse function, voltage-dependent calcium channels, and neuronal signaling. Weighted Gene Co-Expression Network Analysis was then applied and identified a critical module enriched for genes governing lysosome function. By identifying significantly changed gene expression that is associated with lysosomal mechanisms in NHE6-null cells, our analyses suggest that loss of NHE6 function may converge on mechanisms implicated in lysosome-related neurologic disease. Further, this haploid cell model will serve as an important tool for translational science in CS.

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Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Cited by 7 publications

References 64 publications

Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor

Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor

Cystic Fibrosis: Understanding Cystic Fibrosis Transmembrane Regulator Mutation Classification and Modulator Therapies

Targeting NHE6 gene expression identifies lysosome and neurodevelopmental mechanisms in a haploid in vitro cell model

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