Mutation-specific dual potentiators maximize rescue of CFTR gating mutants

Veit, Guido; Fonte, Dillon F. Da; Avramescu, Radu G.; Premchandar, Aiswarya; Bagdány, Miklós; Xu, Haijin; Bensinger, Dennis; Stubba, Daniel; Schmidt, Boris; Matouk, Elias; Lukacs, Gergely L.

doi:10.1016/j.jcf.2019.10.011

Cited by 32 publications

(36 citation statements)

References 41 publications

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“…Viable approaches to further increase the Trikafta therapy efficacy for F508del and rare CFTR mutant correction can be envisioned by implementing (a) triple corrector combinations ( 21 ), (b) combining correctors with a CFTR mRNA stabilizer (PTI428) ( 46 ) or dual potentiator ( 47 , 48 ), (c) increasing the constitutive CFTR activity ( 49 ), and/or (d) using potentiators that do not to compromise the biogenesis and stability of mutant CFTRs ( 35 , 50 ). Selection of modulator combinations, however, requires the knowledge of the mechanism of action of individual CFTR modulators.…”

Section: Discussionmentioning

confidence: 99%

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Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Veit¹,

Roldán²,

et al. 2020

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Based on its clinical benefits, Trikafta — the combination of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor), and the gating potentiator VX-770 (ivacaftor) — was FDA approved for treatment of patients with cystic fibrosis (CF) carrying deletion of phenylalanine at position 508 (F508del) of the CF transmembrane conductance regulator ( CFTR ) on at least 1 allele. Neither the mechanism of action of VX-445 nor the susceptibility of rare CF folding mutants to Trikafta are known. Here, we show that, in human bronchial epithelial cells, VX-445 synergistically restores F508del-CFTR processing in combination with type I or II correctors that target the nucleotide binding domain 1 (NBD1) membrane spanning domains (MSDs) interface and NBD2, respectively, consistent with a type III corrector mechanism. This inference was supported by the VX-445 binding to and unfolding suppression of the isolated F508del-NBD1 of CFTR. The VX-661 plus VX-445 treatment restored F508del-CFTR chloride channel function in the presence of VX-770 to approximately 62% of WT CFTR in homozygous nasal epithelia. Substantial rescue of rare misprocessing mutations (S13F, R31C, G85E, E92K, V520F, M1101K, and N1303K), confined to MSD1, MSD2, NBD1, and NBD2 of CFTR, was also observed in airway epithelia, suggesting an allosteric correction mechanism and the possible application of Trikafta for patients with rare misfolding mutants of CFTR.

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Section: Discussionmentioning

confidence: 99%

“…I sc measurement of polarized HNE has been described previously ( 21 , 48 ). HNE were exposed to compounds or 0.2% DMSO (vehicle control) for 24 hours at 37°C in serum-free PneumaCult-ALI medium (Stemcell Technologies).…”

Section: Methodsmentioning

confidence: 99%

Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Veit¹,

Roldán²,

et al. 2020

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“…In recent years, a considerable effort was focused on molecular therapies that can directly interact with CFTR mutants has indicated the importance of identifying the mutations of CFTR and the complexity of CFTR mutant phenotypes at the cellular levels [ 10 , 30 , 31 ]. Moreover, early diagnosis through NBS is the best way to prevent primary and secondary manifestations of the disease.…”

Section: Discussionmentioning

confidence: 99%

Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey

Bozdoğan

Mujde

Boğa

et al. 2021

Genes

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Background: Cystic fibrosis (CF) is the most common worldwide, life-shortening multisystem hereditary disease, with an autosomal recessive inheritance pattern caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The national newborn screening (NBS) program for CF has been initiated in Turkey since 2015. If the immunoreactive trypsinogen (IRT) is elevated (higher than 70 μg/L in the second control) and confirmed by sweat test or clinical findings, genetic testing is performed. The aims of this study are to emphasize the effect of NBS on the status of genetic diagnosis centers with the increasing numbers of molecular testing methods, and to determine the numbers and types of CFTR mutations in Turkey. Methods: The next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) results of 1595 newborns, who were referred to Cukurova University Adana Genetic Diseases Diagnosis and Treatment Center (AGENTEM) for molecular genetic testing, were evaluated with positive CF NBS program results since 2017. Results: According to the results; 560 (35.1%) of the 1595 patients carried at least 1 (one) CF-related variant, while 1035 patients (64.9%) had no mutation. Compound heterozygosity for two mutations was the most common in patients, while two detected variants were homozygote in 14 patients. A total of 161 variants were detected in 561 patients with mutations. Fifteen novel variants that have not been previously reported were found. Moreover, p.L997F was identified as the most frequent pathogenic mutation that might affect the IRT measurements used for the NBS. The distribution of mutation frequencies in our study showed a difference from those previously reported; for example, the well-known p.F508del was the third most common (n = 42 alleles), rather than the first. The most striking finding is that 313 cases had a pathogenic variant together with the V470M variant, which might have a cumulative effect on CF perpetuation. Conclusion: This study is the first to determine the mutational spectrum of CFTR in correlation with the NBS program in the Turkish population. NBS for CF raises issues regarding screening in diverse populations, both medical and non-medical benefits, and carrier identification. Through the lens of NBS, we focused on the integrated diagnostic algorithms and their effect on the results of genetic testing.

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“…We also show that SBCs act in a synergic manner with VX-770 on several CFTR mutants (F508del, G551D, G970R and G1349D). There are now several studies emphasizing the interest of co-potentiators which act in an additive way or allosterically [8,16,17,[69][70][71], some of them being particularly interesting relative to their lack of interference with corrector activity [8,17], their nanomolar potency and their effect on VX-770 insensitive mutations, such as N1303K and W1282X [16,70]. SBCs remain to be optimized and their effects to be tested compared to other potentiators (for instance Asp11) and against a large panel of CFTR pathogenic mutations, especially those which are not addressed by the recently described class II potentiators, essentially active on mutations in CFTR NBD2 [70].…”

Section: Discussionmentioning

confidence: 99%

Targeting different binding sites in the CFTR structures allows to synergistically potentiate channel activity

Froux

Elbahnsi

Boucherle

et al. 2020

European Journal of Medicinal Chemistry

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Recent evidence shows that combination of correctors and potentiators, such as the drug ivacaftor (VX-770), can significantly restore the functional expression of mutated Cystic Fibrosis Transmembrane conductance Regulator (CFTR), an anion channel which is mutated in cystic fibrosis (CF). The success of these combinatorial therapies highlights the necessity of identifying a broad panel of specific binding mode modulators, occupying several distinct binding sites at structural level. Here, we identified two small molecules, SBC040 and SBC219, which are two efficient cAMP-independent potentiators, acting at low concentration of forskolin with EC50 close to 1 µM and in a synergic way with the drug VX-770 on several CFTR mutants of classes II and III. Molecular dynamics simulations suggested potential SBC binding sites at the vicinity of ATP-binding sites, distinct from those currently proposed for VX-770, outlining SBC molecules as members of a new family of potentiators.

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Mutation-specific dual potentiators maximize rescue of CFTR gating mutants

Cited by 32 publications

References 41 publications

Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination

Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey

Targeting different binding sites in the CFTR structures allows to synergistically potentiate channel activity

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