The antagonism of folate receptor by dolutegravir: developmental toxicity reduction by supplemental folic acid
The antagonism of folate receptor by dolutegravir: developmental toxicity reduction by supplemental folic acid
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DOI：
10.1097/qad.0000000000002289
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发表时间：
2019-11-01
期刊：
影响因子：
3.8
通讯作者：
Finnell, Richard H.
中科院分区：
文献类型：
--
作者：
Cabrera, Robert M.;Souder, Jaclyn P.;Finnell, Richard H.
目的：母体叶酸（维生素B 9）状态是已知的神经管缺陷风险的最大调节剂，因此我们评估了叶酸相关的dolutegravir（DTG）发育毒性作用机制。设计图：使用蛋白质和细胞相互作用研究和动物模型，将叶酸受体1（FOLR 1）作为DTG发育毒性的靶点进行检查。方法：采用FOLR 1竞争性结合研究检测DTG对FOLR 1的拮抗作用。人胎盘细胞系研究用于测试与DTG、叶酸和阳离子的相互作用。选择斑马鱼作为动物模型来研究DTG诱导的发育毒性和拯救策略。结果：FOLR 1结合研究表明DTG在治疗浓度下是一种非竞争性FOLR 1拮抗剂。体外试验表明，钙（2 mmol/l）可增加FOLR 1-叶酸相互作用，并改变DTG-FOLR 1-叶酸相互作用和细胞毒性。DTG不通过二氢叶酸还原酶抑制下游叶酸代谢。胚胎早期暴露于DTG对斑马鱼具有发育毒性，补充叶酸可减轻DTG的发育毒性。结论：叶酸和FOLR 1是神经管缺陷风险的既定修饰剂，结合数据表明DTG是FOLR 1的部分拮抗剂。补充叶酸可改善DTG对斑马鱼的发育毒性。这些研究的结果有望为未来的动物模型和育龄妇女基于DTG的抗逆转录病毒治疗的临床研究提供信息和指导。
Objective: Maternal folate (vitamin B9) status is the largest known modifier of neural tube defect risk, so we evaluated folate-related mechanisms of action for dolutegravir (DTG) developmental toxicity. Design: Folate receptor 1 (FOLR1) was examined as a target for DTG developmental toxicity using protein and cellular interaction studies and an animal model. Methods: FOLR1 competitive binding studies were used to test DTG for FOLR1 antagonism. Human placenta cell line studies were used to test interactions with DTG, folate, and cations. Zebrafish were selected as an animal model to examine DTG-induced developmental toxicity and rescue strategies. Results: FOLR1 binding studies indicate DTG is a noncompetitive FOLR1 antagonist at therapeutic concentrations. In-vitro testing indicates calcium (2 mmol/l) increases FOLR1-folate interactions and alters DTG-FOLR1-folate interactions and cytotoxicity. DTG does not inhibit downstream folate metabolism by dihydrofolate reductase. Early embryonic exposure to DTG is developmentally toxic in zebrafish, and supplemental folic acid can mitigate DTG developmental toxicity. Conclusion: Folates and FOLR1 are established modifiers of risk for neural tube defects, and binding data indicates DTG is a partial antagonist of FOLR1. Supplemental folate can ameliorate increased developmental toxicity due to DTG in zebrafish. The results from these studies are expected to inform and guide future animal models and clinical studies of DTG-based antiretroviral therapy in women of childbearing age.