Phospholipidosis, the excessive accumulation of phospholipids within lysosomes, is a pathological response observed following exposure to many drugs across multiple therapeutic groups. A clear mechanistic understanding of the causes and implications of this form of drug toxicity has remained elusive. We previously reported the discovery and characterization of a lysosome specific phospholipase A2 (PLA2G15), and later reported that amiodarone, a known cause of drug-induced phospholipidosis, inhibits this enzyme. Here, we assayed a library of 163 drugs was assayed for inhibition of PLA2G15 to determine whether this phospholipase was the cellular target for therapeutics other than amiodarone that cause phospholipidosis. We observed that 144 compounds inhibited PLA2G15 activity. Thirty-six compounds not previously reported to cause phospholipidosis inhibited PLA2G15 with IC₅₀ values less than 1 mM, and were confirmed to cause phospholipidosis in an in vitro assay. Within this group, fosinopril was the most potent inhibitor (IC₅₀ 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 to 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.

中文翻译：

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溶酶体磷脂酶 A2 的抑制可预测药物诱导的磷脂病。

磷脂病，即溶酶体内磷脂的过度积累，是在多个治疗组暴露于多种药物后观察到的病理反应。对这种形式的药物毒性的原因和影响的明确机制理解仍然难以捉摸。我们之前报道了溶酶体特异性磷脂酶 A2 (PLA2G15) 的发现和表征，后来报道了胺碘酮，一种已知的药物诱导性磷脂病的原因，可抑制这种酶。在这里，我们分析了 163 种药物库对 PLA2G15 的抑制作用，以确定这种磷脂酶是否是除胺碘酮以外的导致磷脂沉积的治疗剂的细胞靶标。我们观察到 144 种化合物抑制 PLA2G15 活性。_{50 个}值小于 1 mM，并在体外测定中证实会导致磷脂病。在该组中，福辛普利是最有效的抑制剂 (IC ₅₀ 0.18 μM)。福辛普利抑制 PLA2G15 的其他特征与 PLA2G15 与脂质体结合的干扰一致。与基于 pKa 和 ClogP 的计算机模型相比，PLA2G15 抑制在预测磷脂沉积方面更准确，分别测量溶酶体中的质子化和不依赖运输的分布。总之，PLA2G15 是导致磷脂沉积的阳离子两亲药物的主要靶点，阳离子两亲化合物对 PLA2G15 的抑制为药物开发过程中的潜在毒性提供了潜在的稳健筛选平台。