Identification of novel F508del-CFTR traffic correctors among triazole derivatives

Bacalhau, Mafalda; Ferreira, F. Castela; Kmit, Arthur; Souza, Felipe Rodrigues de; Silva, Verônica D. da; Pimentel, André Silva; Amaral, M.D.; Buarque, Camilla D.; Lopes‐Pacheco, Miquéias

doi:10.1016/j.ejphar.2022.175396

Cited by 5 publications

(3 citation statements)

References 66 publications

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“…Although the R334W mutation causes neither folding nor trafficking impairment, some studies have demonstrated that R334W-CFTR-dependent chloride secretion can be enhanced by increasing the number of R334W-CFTR channels at the plasma membrane with correctors, such as VX-809 and VX-661 [ 39 , 40 , 46 , 61 ]. In a recent report, intestinal organoids from an individual with CF (1677delTA/R334W) were incubated with VX-770, VX-809/VX-770, VX-661/VX-770 and VX-445/VX-661/VX-770 [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…A new CFBE cell line stably co-expressing the HS-YFP (F46L/H148Q/I152L) and R334W-CFTR was generated. Briefly, the HS-YFP cloned into the pcDNA3.1 expression vector was re-cloned into the lentiviral expression vector pLVX-Puro and then transfected into the HEK-293T cells to produce the lentiviral particles [ 39 ]. After 48 h, these particles were harvested and transduced into CFBE cells expressing R334W-CFTR [ 40 ].…”

Section: Methodsmentioning

confidence: 99%

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Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Bacalhau

Ferreira

Silva

et al. 2023

JPM

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The R334W (c.1000C>T, p.Arg334Trp) is a rare cystic fibrosis (CF)-causing mutation for which no causal therapy is currently approved. This mutation leads to a significant reduction of CF transmembrane conductance regulator (CFTR) channel conductance that still allows for residual function. Potentiators are small molecules that interact with CFTR protein at the plasma membrane to enhance CFTR-dependent chloride secretion, representing thus pharmacotherapies targeting the root cause of the disease. Here, we generated a new CF bronchial epithelial (CFBE) cell line to screen a collection of compounds and identify novel potentiators for R334W-CFTR. The active compounds were then validated by electrophysiological assays and their additive effects in combination with VX-770, genistein, or VX-445 were exploited in this cell line and further confirmed in intestinal organoids. Four compounds (LSO-24, LSO-25, LSO-38, and LSO-77) were active in the functional primary screen and their ability to enhance R334W-CFTR-dependent chloride secretion was confirmed using electrophysiological measurements. In silico ADME analyses demonstrated that these compounds follow Lipinski’s rule of five and are thus suggested to be orally bioavailable. Dose–response relationships revealed nevertheless suboptimal efficacy and weak potency exerted by these compounds. VX-770 and genistein also displayed a small potentiation of R334W-CFTR function, while VX-445 demonstrated no potentiator activity for this mutation. In the R334W-expressing cell line, CFTR function was further enhanced by the combination of LSO-24, LSO-25, LSO-38, or LSO-77 with VX-770, but not with genistein. The efficacy of potentiator VX-770 combined with active LSO compounds was further confirmed in intestinal organoids (R334W/R334W genotype). Taken together, these molecules were demonstrated to potentiate R334W-CFTR function by a different mechanism than that of VX-770. They may provide a feasible starting point for the design of analogs with improved CFTR-potentiator activity.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

Bacalhau

Ferreira

Silva

et al. 2023

JPM

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“…The MoA of novel compounds can be assessed by investigating their possible additive effects to previously characterized CFTR genetic revertants. While validating p.Phe508del rescue by novel correctors among triazole compounds, Bacalhau and colleagues [ 127 ] evaluated elexacaftor as a positive control for this rescue. The authors found that elexacaftor was additive to p.Gly550Glu, p.Arg1070Trp and 4RK in rescuing p.Phe508del processing and function, thus evidencing a distinct MoA for this modulator, not acting on the NBD1:NBD2 interface or the NBD1:ICL4 interface nor the arginine frame tripeptide-dependent ER retention mechanisms, respectively [ 127 ].…”

Section: Elexacaftor (Vx-445) and Triple Combination With Tezacaftor ...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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