Pharmacological induction of CFTR function in patients with cystic fibrosis: mutation-specific therapy.

摘要: CFTR mutations cause defects of protein production and function by different molecular mechanisms. Mutations can be classified according to the mechanisms which they disrupt function. This understanding dysfunction provides scientific basis for development targeted drugs mutation-specific therapy cystic fibrosis (CF). Class I are nonsense that result in presence a premature stop codon leads unstable mRNA, or release from ribosome short, truncated is not functional. Aminoglycoside antibiotics suppress termination codons disrupting translational fidelity allowing incorporation an amino acid, thus permitting translation continue normal transcript. II impairment processing folding Golgi. As result, mutant retained endoplasmic reticulum (ER) eventually degradation quality control Chemical chaperones such as sodium-4-phenylbutyrate stabilize structure, allow it escape ER transported cell membrane. III regulatory domain. resistant phosphorylation adenosine tri-phosphate (ATP) binding. activators alkylxanthines (CPX) flavonoid genistein overcome affected ATP binding through direct nucleotide fold. In patients carrying class IV mutations, results reduced chloride transport. Increases overall surface content these mutants might relative reduction conductance. Alternatively, restoring native pore characteristics pharmacologically effective. Activators at plasma membrane may promoting phosphorylation, blocking dephosphorylation, interacting directly with CFTR, and/or modulation protein-protein interactions. V affect splicing machinery generate both aberrantly correctly spliced transcripts, levels vary among organs same patient. Splicing factors promote exon inclusion skipping increases depending on defect. Inconsistent were reported regarding required level corrected mutated had reached order achieve