The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia

Abstract

Cystic fibrosis (CF), a genetic disease caused by mutations in the CFTR gene, is a life-limiting disease characterized by chronic bacterial airway infection and severe inflammation. Some CFTR mutants have reduced responsiveness to cAMP/PKA signaling; hence, pharmacological agents that elevate intracellular cAMP are potentially useful for the treatment of CF. By inhibiting cAMP breakdown, phosphodiesterase (PDE) inhibitors stimulate CFTR in vitro and in vivo. Here, we demonstrate that PDE inhibition by RPL554, a drug that has been shown to cause bronchodilation in asthma and chronic obstructive pulmonary disease (COPD) patients, stimulates CFTR-dependent ion secretion across bronchial epithelial cells isolated from patients carrying the R117H/F508del CF genotype. RPL554-induced CFTR activity was further increased by the potentiator VX-770, suggesting an additional benefit by the drug combination. RPL554 also increased cilia beat frequency in primary human bronchial epithelial cells. The results indicate RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF.

A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD

“…Whereas the effects of ensifentrine on bronchodilation were apparent from the first dose, there was a gradual improvement in symptoms (E-RS™:COPD). This further highlights the often poor association between FEV 1 and patient reported outcomes, and in this case indicates that the improvement of persistent symptoms The rapid bronchodilation observed is consistent with previous short-term ensifentrine studies in COPD, and with preclinical evidence of the direct effect of ensifentrine on large and small airways, including increased mucociliary clearance and bronchial relaxation [17][18][19]. In particular, ensifentrine had a substantial effect on peak FEV 1 , with differences vs placebo at Week 4 between 139 and 200 mL; these improvements were consistent with the effects on FEV 1 averaged over 12 h. The more progressive improvement in symptoms (especially breathlessness) could, at least in part, be due to a reduction in hyperinflation.…”

Potentiation of the cystic fibrosis transmembrane conductance regulator Cl−channel by ivacaftor is temperature independent

“…Because the cellular ATP concentration exceeds the substrate concentration required for half maximal activity for CFTR regulation by ATP and inhibition by ADP is likely to be weak at cellular concentrations (6,7,64), the balance of protein kinase and phosphatase activity predominantly controls CFTR activity in vivo (28). This highlights the therapeutic potential of small molecules that promote the phosphorylation of CFTR by PKA [e.g., RPL554 (66)]. Importantly, following CFTR phosphorylation by PKA, ivacaftor potentiates both ATP-dependent and ATP-independent CFTR channel gating (26,37), highlighting its value in the treatment of CF (54,59).…”

Cigarette Smoke‐Induced Acquired Dysfunction of Cystic Fibrosis Transmembrane Conductance Regulator in the Pathogenesis of Chronic Obstructive Pulmonary Disease

“…In addition to roflumilast and ivacaftor, the next generation of potentiators targeting the CFTR gating defect in smoke-exposed human tissues and CFTR correctors (VX809, lumacaftor, and ABBV/GLPG-2222) restoring and/or enhancing CFTR trafficking to cell surface may provide novel strategies in COPD treatments [ 87 ]. Moreover, the combination of CFTR potentiator with CFTR corrector and/or PDE inhibitor may synergistically increase the effect of the restoration of CFTR function [ 78 , 88 ]. For example, the CFTR potentiator VX-770 (ivacaftor) was found to further enhance dual PDE3/4 inhibitor RPL554-induced CFTR activity in primary HBECs [ 78 ].…”

“…In this regard, selective PDE4 and dual PDE3/4 inhibitors have anti-inflammatory and bifunctional bronchodilator effects in a preclinical study [ 77 ]. In this regard, the dual PDE3/4 inhibitor RPL554 has exhibited an ability to activate CFTR-dependent ion secretion in human primary bronchial epithelial cultures of CF patient carrying the R117H/F508del mutations [ 78 ]. To date, however, only one selective PDE4 inhibitor, the orally active roflumilast, has been licensed for the treatment of CB form of COPD [ 79 ].…”