Inhibition of lysosomal phospholipase A2 predicts drug-induced phospholipidosis
Vania Hinkovska‐Galcheva, Taylour Treadwell, Jonathan M. Shillingford, Angela Lee, Akira Abe, J.J.G. Tesmer, James A. Shayman
Abstract
0.18 μM). Additional characterization of the inhibition of PLA2G15 by fosinopril was consistent with interference of PLA2G15 binding to liposomes. PLA2G15 inhibition was more accurate in predicting phospholipidosis compared with in silico models based on pKa and ClogP, measures of protonation, and transport-independent distribution in the lysosome, respectively. In summary, PLA2G15 is a primary target for cationic amphiphilic drugs that cause phospholipidosis, and PLA2G15 inhibition by cationic amphiphilic compounds provides a potentially robust screening platform for potential toxicity during drug development.
Topics & Concepts
PhospholipidosisLysosomePharmacologyChemistryDrugEnalaprilatMechanism of actionIC50In vitroBiochemistryPhospholipidEnzymeBiologyACE inhibitorEndocrinologyAngiotensin-converting enzymeMembraneBlood pressureLysosomal Storage Disorders ResearchVenomous Animal Envenomation and StudiesNeonatal Health and Biochemistry