Use of Potentiators and Correctors to Rescue the Various Effects of Mutations in Cystic Fibrosis

Abstract

Cystic fibrosis, a severe autosomal recessive disorder due to presence of mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. To date about 2000 mutations established in CFTR gene worldwide. All the mutations have been categorized into six subgroups accordingly to their effects on CFTR protein expression, structure and functions. ∆F508 commonest mutation due to the deletion of phenylalanine from 508 position in the nucleotide binding domain of CFTR protein which leads to misfolding as well as expression at plasma membrane and, chloride gating channel and stability. The molecules that target the underlying defect in CFTR protein which are categorized into three main types of modulators viz correctors, potentiators and amplifiers. These molecules are able to restore chloride flow, thereby they can improve CF manifestations enough to relieve symptoms associated with CF. The molecular and cellular mechanism underlying cystic fibrosis is utmost important for targeting the molecular defect for CF treatment. Corrector molecules target the misfolding/misprocessing process in response to ΔF508 mutation whereas potentiators are able to restore cAMP dependent chloride channel activity of mutant CFTR at the plasma membranes. Particular attention is corroborated to reestablish the molecular defect using new therapeutic molecules. Recently, new advances are reported which are indicative of more potent therapy in CF using third generation modulators