Elexacaftor/tezacaftor/ivacaftor (Trikafta) is transformative therapy for cystic fibrosis. The F508del CFTR mutation causes which protein folding defect corrected by elexacaftor/tezacaftor?

• A F508del creates a premature stop codon causing CFTR mRNA nonsense decay; elexacaftor suppresses this nonsense mutation
• B F508del causes a splicing defect reducing CFTR mRNA levels; elexacaftor corrects the splice site
• C F508del reduces CFTR channel conductance; all three drugs collectively increase single-channel Cl- conductance
• D F508del deletes phenylalanine at position 508 in NBD1 domain, causing misfolding and ER-associated degradation; elexacaftor (corrector 1) and tezacaftor (corrector 2) bind different CFTR domain interfaces to stabilize the protein, while ivacaftor (potentiator) opens the channel at the cell surface ✓

Explanation

The F508del mutation (deletion of phenylalanine-508 in nucleotide-binding domain 1, NBD1) causes CFTR protein misfolding. The misfolded F508del CFTR is retained in the endoplasmic reticulum and degraded by ER quality control machinery (ERAD), with very little reaching the cell surface. Even when rescued to the surface, F508del CFTR has impaired channel gating. Elexacaftor is a 'next-generation corrector' that binds the interface between membrane-spanning domain 1 (MSD1) and NBD2, stabilizing the protein. Tezacaftor binds MSD1 at a different site, providing complementary stabilization. Together they dramatically increase CFTR trafficking to the plasma membrane. Ivacaftor (potentiator) then keeps the channel open longer at the cell surface by binding the transmembrane domain and enhancing ATP-dependent gating.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.