CFTR is a chloride channel, that controls ion and water secretion and absorption in epithelial tissues. CFTR protein dysfunction leads to abnormal ion transport across the airway epithelium[3]. PPQ2 as a small molecule CFTR inhibitor that completely inhibited CFRR chloride current with IC50 value of 90 nM[4]. In vitro, PPQ-102 at the dose of 10µM inhibited CFTR almost 100% in (nonpermeabilized) human intestinal (T84) and bronchial cells following maximal CFTR activation by forskolin and IBMX. However, PPQ-102 did not inhibit calcium-activated chloride channels or cellular cAMP production[4]. PPQ-102 also inhibited the volume-regulated anion channel (VRAC) conductance with IC50 value of 20μM in HEK293 cells[5]. Treatment of NCI-H292 cells with 10μM PPQ-102 induced a two-fold increase in VEGF-A synthesis[3]. In the presence of NADPH, PPQ-102 lost in hepatic microsomes about 60% within 30min. No loss of PPQ-102 was seen in the absence of NADPH. In vivo, PPQ-102 was undetectable in serum, kidney and urine at 30-60 min after intravenous administration of 300μg PPQ-102 by LC/MS assay with sensitivity better than 100nM[6].
作用机制
PPQ-102 inhibits CFTR by an altered channel gating mechanism, with stabilization of the channel closed state[4].
PPQ-102 细胞实验
Cell Line
Concentration
Treated Time
Description
References
NPTr cells
30 µM
2 hours
Inhibition of VRAC activity, reducing CDT-induced apoptosis in NPTr cells
Virulence. 2023 Dec;14(1):2287339
CFBE41o- WT cells
0.1, 1, 5, 10, 20, 30 µM
48 hours
To evaluate the anti-SARS-CoV-2 activity of PPQ-102. Results showed that PPQ-102 inhibited SARS-CoV-2 replication by nearly 100% at 30 μM, with an IC50 of 15.92 μM.
Cells. 2023 Feb 28;12(5):776
HEK-293 cells
10 µM and 30 µM
5 minutes
Test the inhibitory effect of PPQ-102 on VRAC/LRRC8-mediated chloride conductance, with an IC50 value of 19.6±1.5 μM
Front Pharmacol. 2017 May 31;8:328
PPQ-102 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Polycystic kidney disease model
Added to culture medium
0.5 µM, 2.5 µM, 5 µM
Medium replaced every 12 hours for 4 days
Evaluating PPQ-102 inhibition of cyst formation, 0.5 μM PPQ-102 inhibited cyst formation by ~60%, and 2.5 μM and 5 μM PPQ-102 nearly completely inhibited cyst formation.
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