Combination potentiator (‘co-potentiator’) therapy for CF caused by CFTR mutants, including N1303K, that are poorly responsive to single potentiators
| Autor: | Peter M. Haggie, Walter E. Finkbeiner, Joseph-Anthony Tan, Alan S. Verkman, Dennis W. Nielson, Jung-Ho Son, Luis J. V. Galietta, Mark J. Kurth, Lorna Zlock, Puay-Wah Phuan, Ilaria Musante, Clarabella J. Li |
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| Přispěvatelé: | Phuan, Puay-Wah, Son, Jung-Ho, Tan, Joseph-Anthony, Li, Clarabella, Musante, Ilaria, Zlock, Lorna, Nielson, Dennis W., Finkbeiner, Walter E., Kurth, Mark J., Galietta, Luis J., Haggie, Peter M., Verkman, Alan S. |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cystic Fibrosis High-throughput screen Respiratory System Mutant Cystic Fibrosis Transmembrane Conductance Regulator Quinolones Pharmacology Aminophenols medicine.disease_cause Cystic fibrosis Congenital 0302 clinical medicine CFTR Lung Sulfonamides Mutation Cultured Drug Synergism respiratory system Small molecule Potentiator Cystic fibrosi N1303K Ion Channel Gating Pulmonary and Respiratory Medicine Agonist congenital hereditary and neonatal diseases and abnormalities medicine.drug_class Cells Clinical Sciences Article Cell Line Structure-Activity Relationship 03 medical and health sciences Rare Diseases medicine Animals Humans Structure–activity relationship business.industry medicine.disease 030104 developmental biology 030228 respiratory system Cell culture Pediatrics Perinatology and Child Health Mutant Proteins business |
| Zdroj: | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, vol 17, iss 5 |
| ISSN: | 1569-1993 |
| DOI: | 10.1016/j.jcf.2018.05.010 |
| Popis: | Background Current modulator therapies for some cystic fibrosis-causing CFTR mutants, including N1303K, have limited efficacy. We provide evidence here to support combination potentiator (co-potentiator) therapy for mutant CFTRs that are poorly responsive to single potentiators. Methods Functional synergy screens done on N1303K and W1282X CFTR, in which small molecules were tested with VX-770, identified arylsulfonamide-pyrrolopyridine, phenoxy-benzimidazole and flavone co-potentiators. Results A previously identified arylsulfonamide-pyrrolopyridine co-potentiator (ASP-11) added with VX-770 increased N1303K-CFTR current 7-fold more than VX-770 alone. ASP-11 increased by ~65% of the current of G551D-CFTR compared to VX-770, was additive with VX-770 on F508del-CFTR, and activated wild-type CFTR in the absence of a cAMP agonist. ASP-11 efficacy with VX-770 was demonstrated in primary CF human airway cell cultures having N1303K, W1282X and G551D CFTR mutations. Structure-activity studies on 11 synthesized ASP-11 analogs produced compounds with EC 50 down to 0.5 μM. Conclusions These studies support combination potentiator therapy for CF caused by some CFTR mutations that are not effectively treated by single potentiators. |
| Databáze: | OpenAIRE |
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