A novel triple combination of pharmacological chaperones improves F508del-CFTR correction

Carlile, Graeme W.; Yang, Qi; Matthes, Elizabeth; Liao, Jie; Radinovic, Stevo; Miyamoto, Carol M.; Robert, Renaud; Hanrahan, John W.; Thomas, David Y.

doi:10.1038/s41598-018-29276-y

Cited by 33 publications

(39 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Figure 2 A shows the F508del-CFTR corrector activity in the high-throughput screening (HTS) cell-based assay upon treatment with (i) 10 μM latonduine A ( 1 ), (ii) 10 μM compound 5 , (iii) 10 μM compound 6 , (iv) 10 μM of both compounds 5 and 6 , and (v) VX809 at 1 μM as a positive control. 34 The results show that neither compound 5 or 6 alone gives F508del-CFTR correction but that a 1:1 combination of the two selective PARP inhibitors 5 and 6 generates F508del-CFTR trafficking correction virtually identical to latonduine A ( 1 ) alone in the HTS assay.…”

Section: Results and Discussionmentioning

confidence: 95%

Combination of Selective PARP3 and PARP16 Inhibitory Analogues of Latonduine A Corrects F508del-CFTR Trafficking

Centko¹,

Carlile

Barne³

et al. 2020

ACS Omega

Self Cite

View full text Add to dashboard Cite

The marine natural product latonduine A ( 1 ) shows F508del-cystic fibrosis transmembrane regulator (CFTR) corrector activity in cell-based assays. Pull-down experiments, enzyme inhibition assays, and siRNA knockdown experiments suggest that the F508del-CFTR corrector activities of latonduine A and a synthetic analogue MCG315 ( 4 ) result from simultaneous inhibition of PARP3 and PARP16. A library of synthetic latonduine A analogs has been prepared in an attempt to separate the PARP3 and PARP16 inhibitory properties of latonduine A with the goal of discovering selective small-molecule PARP3 and PARP16 inhibitory cell biology tools that could confirm the proposed dual-target F508del-CFTR corrector mechanism of action. The structure activity relationship (SAR) study reported herein has resulted in the discovery of the modestly potent (IC 50 3.1 μM) PARP3 selective inhibitor (±)-5-hydroxy-4-phenyl-2,3,4,5-tetrahydro-1 H -benzo[ c ]azepin-1-one ( 5 ) that shows 96-fold greater potency for inhibition of PARP3 compared with its inhibition of PARP16 in vitro and the potent (IC 50 0.362 μM) PARP16 selective inhibitor (±)-7,8-dichloro-5-hydroxy-4-(pyridin-2-yl)-2,3,4,5-tetrahydro-1 H -benzo[ c ]azepin-1-one ( 6 ) that shows 205-fold selectivity for PARP16 compared with PARP3 in vitro . At 1 or 10 μM, neither 5 or 6 alone showed F508del-CFTR corrector activity, but when added together at 1 or 10 μM each, the combination exhibited F508del-CFTR corrector activity identical to 1 or 10 μM latonduine A ( 1 ), respectively, supporting its novel dual PARP target mechanism of action. Latonduine A ( 1 ) showed additive in vitro corrector activity in combination with the clinically approved corrector VX809, making it a potential new partner for cystic fibrosis combination drug therapies.

show abstract

Section: Results and Discussionmentioning

confidence: 95%

Combination of Selective PARP3 and PARP16 Inhibitory Analogues of Latonduine A Corrects F508del-CFTR Trafficking

Centko¹,

Carlile

Barne³

et al. 2020

ACS Omega

Self Cite

View full text Add to dashboard Cite

show abstract

“…This ). Two studies have also proposed that Lumacaftor can bind NBD1 [11,51]. Finally, putative binding sites of type III correctors (acting on NBD1 folding/stability) can be searched at the surface of (or buried within) NBD1.…”

Section: Discussionmentioning

confidence: 99%

“…Occupation of these sites may moreover lead to a general rescue of mutated proteins through allostery [10]. Along these lines, a triple combination of pharmacological chaperones (VX-809, RDR1 and MCG1516A) has also recently been reported, the three correctors having however been proposed to interact with NBD1 [11]. The importance of binding multiple sites for correction is now also underscored by the recent report of improved clinical efficiency when adding to ivacaftor (VX-770) + tezacaftor (VX-661) bitherapy new generation correctors (VX-445 and VX-659) targeting distinct sites of the protein [12,13].…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…We tested next whether ASO- could improve chloride secretion, as defined by a forskolin-stimulated and bumetanide-inhibited Ieq, in primary human bronchial epithelial (hBE) cells isolated from lung explants of CF patients (46)(47)(48). Cells derived from two patients compound heterozygous for CFTR c.3718-2477C>T and F508del-CFTR (donors 1 and 2) and one homozygous for the splice mutation (donor 3) were tested.…”

Section: Aso- Improves Chloride Secretion In Human Bronchial Epithelmentioning

confidence: 99%

Antisense oligonucleotide-mediated correction ofCFTRsplicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

Michaels

Bridges

Hastings

2020

Preprint

View full text Add to dashboard Cite

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding an anion channel that conducts chloride and bicarbonate across epithelial membranes. Mutations that disrupt pre-mRNA splicing occur in more than 15% of CF cases. One common CFTR splicing mutation is CFTR c.3718-2477C>T (3849+10kbC>T), which creates a new 5' splice site, resulting in splicing to a cryptic exon with a premature termination codon.Splice-switching antisense oligonucleotides (ASOs) have emerged as an effective therapeutic strategy to block aberrant splicing. We test an ASO targeting the CFTR c.3718-2477C>T mutation and show that it effectively blocks aberrant splicing in primary bronchial epithelial (hBE) cells from CF patients with the mutation. ASO treatment results in long-term improvement in CFTR activity in hBE cells, as demonstrated by a recovery of chloride secretion and apical membrane conductance.We also show that the ASO is more effective at recovering chloride secretion in our assay than ivacaftor, the potentiator treatment currently available to these patients.Our findings demonstrate the utility of ASOs in correcting CFTR expression and channel activity in a manner expected to be therapeutic in patients.

show abstract

A novel triple combination of pharmacological chaperones improves F508del-CFTR correction

Cited by 33 publications

References 65 publications

Combination of Selective PARP3 and PARP16 Inhibitory Analogues of Latonduine A Corrects F508del-CFTR Trafficking

Combination of Selective PARP3 and PARP16 Inhibitory Analogues of Latonduine A Corrects F508del-CFTR Trafficking

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

Antisense oligonucleotide-mediated correction ofCFTRsplicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

Contact Info

Product

Resources

About