PTI-428

PTI-428 is a specific modulator that enhances and stabilizes the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein^[1]. CFTR is a protein located on the surface of epithelial cells, acting as an ion channel responsible for regulating the transmembrane transport of chloride and bicarbonate ions, thereby maintaining salt and water balance in mucus^[2,3]. PTI-428 is typically used in combination with correctors and other agents for the treatment and research of cystic fibrosis^[4,5].

In vitro, treatment of F508del-CFTR-expressing CFBE41o cells with PTI-428 (10-100μM) for 24h dose-dependently enhances CFTR function, showing synergistic effects when combined with VX-809^[6]. PTI-428 (10μM) treatment of primary human F508del CF bronchial epithelial (CFBE) cells for 24h reverses the elexacaftor/tezacaftor/ivacaftor (ETI)-corrected CFTR functional decline induced by transforming growth factor-beta 1 (TGF-β1) and restores CFTR mRNA expression levels^[7]. Pretreatment of human bronchial epithelial cells (HBECs) derived from patients with chronic obstructive pulmonary disease (COPD) with PTI-428 (10μM) for 24h, followed by exposure to cigarette smoke (CS) for 4h, significantly rescues CS-induced CFTR channel dysfunction, improves mucus viscosity, and restores ciliary beat frequency^[8].

References:
[1] GIRÓN MORENO R M, GARCÍA-CLEMENTE M, DIAB-CÁCERES L, et al. Treatment of pulmonary disease of cystic fibrosis: A comprehensive review[J]. Antibiotics, 2021, 10(5): 486.
[2] BOROWITZ D. CFTR, bicarbonate, and the pathophysiology of cystic fibrosis[J]. Pediatric Pulmonology, 2015, 50(S40): S24-S30.
[3] HANSSENS L S, DUCHATEAU J, CASIMIR G J. CFTR protein: not just a chloride channel?[J]. Cells, 2021, 10(11): 2844.
[4] LOPES-PACHECO M. CFTR modulators: the changing face of cystic fibrosis in the era of precision medicine[J]. Frontiers in Pharmacology, 2020, 10: 1662.
[5] MITRI C, XU Z, BARDIN P, et al. Novel anti-inflammatory approaches for cystic fibrosis lung disease: identification of molecular targets and design of innovative therapies[J]. Frontiers in Pharmacology, 2020, 11: 1096.
[6] VENTURINI A, BORRELLI A, MUSANTE I, et al. Comprehensive analysis of combinatorial pharmacological treatments to correct nonsense mutations in the CFTR gene[J]. International Journal of Molecular Sciences, 2021, 22(21): 11972.
[7] BENGTON C, SILSWAL N, BA UMLIN N, et al. The CFTR amplifier nesolicaftor rescues TGF-β1 inhibition of modulator-corrected F508del CFTR function[J]. International Journal of Molecular Sciences, 2022, 23(18): 10956.
[8] SILSWAL N, BA UMLIN N, HAWORTH S, et al. Therapeutic strategies to reverse cigarette smoke-induced ion channel and mucociliary dysfunction in COPD airway epithelial cells[J]. American Journal of Physiology-Lung Cellular and Molecular Physiology, 2025, 328(4): L571-L585.

PTI-428是一种可增强并稳定囊性纤维化跨膜传导调节因子（CFTR）蛋白功能的特异性调节剂^[1]。CFTR是一种位于上皮细胞表面的蛋白质，它作为离子通道，负责调控氯离子和碳酸氢根离子的跨膜转运，从而维持黏液中的盐水平衡^[2,3]。PIT-428通常与校正剂等试剂联合使用用于囊性纤维化的治疗和研究^[4,5]。

在体外，PTI-428（10-100μM）处理表达F508del-CFTR的CFBE41o细胞24h，可剂量依赖性地增强CFTR功能，且与VX-809联用有协同效应^[6]。PTI-428（10μM）处理原代人F508del CF支气管上皮（CFBE）细胞24h，逆转了转化生长因子-β1（TGF-β1）引起的elexacaftor/tezacaftor/ivacaftor（ETI）校正CFTR功能下降，并恢复了CFTR mRNA的表达水平^[7]。PTI-428（10μM）预处理慢性阻塞性肺疾病（COPD）患者来源的人支气管上皮细胞（HBECs）24h，随后暴露于香烟浓雾（CS）4h，显著挽救了CS引起的CFTR通道功能下降，并改善了粘液粘度，恢复了纤毛摆动频率^[8]。