Peptide CIGB-552 has a synergistic effect on CFTR-F508del when combined with elexacaftor/tezacaftor/ivacaftor triple therapy for cystic fibrosis.

Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene, leading to progressive respiratory decline and reduced life expectancy. The most common mutation, CFTR-F508del, results in mislocalised and non-functional protein. Although triple therapy with elexacaftor/tezacaftor/ivacaftor (ETI) is prescribed for patients carrying this mutation, some biological defects remain unresolved. We previously identified COMMD1 as a potential therapeutic target, as its overexpression enhances CFTR-WT plasma membrane localisation. CIGB-552, a cell-penetrating peptide discovered in 2013, stabilises COMMD1. This study evaluates its therapeutic potential in cystic fibrosis. CIGB-552 was tested, with and without ETI, in CFBE and HEK cells stably expressing CFTR-WT or CFTR-F508del, and in primary human bronchial cells. CFTR function was assessed using YFP quenching and short-circuit current assays. Peptide uptake was evaluated using FITC-labelled CIGB-552 in submerged and air-liquid interface models. Plasma membrane density of CFTR was measured in CFBE CFTR-HA cells, and western blotting assessed CFTR maturation and COMMD1 expression. CIGB-552 was non-toxic and preferentially entered CFBE CFTR-F508del cells rather than CFBE CFTR-WT cells, without altering COMMD1 expression or localisation. Although not a corrector or potentiator alone, CIGB-552 synergised with ETI, enhancing CFTR-F508del-mediated chloride efflux, confirmed in primary cells. CIGB-552 also increased YFP quenching of CFTR-WT and CFTR-G551D, in combination with ivacaftor. This effect required COMMD1. COMMD1 expression was necessary for CIGB-552 to affect CFTR function positively. Its synergy with the triple therapy offers a promising strategy for improving CF treatment.