Targeting Glial Cells by Organic Anion-Transporting Polypeptide 1C1 (OATP1C1)-Utilizing l-Thyroxine-Derived Prodrugs,Journal of Medicinal Chemistry

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Targeting Glial Cells by Organic Anion-Transporting Polypeptide 1C1 (OATP1C1)-Utilizing l-Thyroxine-Derived Prodrugs
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-06 , DOI: 10.1021/acs.jmedchem.3c01026
Arun Kumar Tonduru ₁ , Seyed Hamed Maljaei ₁ , Santosh Kumar Adla ₁ , Landry Anamea ₁ , Janne Tampio ₁ , Adéla Králová ₁ , Aaro J Jalkanen ₁ , Catarina Espada ₁ , Inês Falcato Santos ₁ , Ahmed B Montaser ₁ , Jarkko Rautio ₁ , Thales Kronenberger _{1,

2,

3} , Antti Poso _{1,

2,

3,

4,

5} , Kristiina M Huttunen ₁

Affiliation

OATP1C1 (organic anion-transporting polypeptide 1C1) transports thyroid hormones, particularly thyroxine (T₄), into human astrocytes. In this study, we investigated the potential of utilizing OATP1C1 to improve the delivery of anti-inflammatory drugs into glial cells. We designed and synthesized eight novel prodrugs by incorporating T₄ and 3,5-diiodo-l-tyrosine (DIT) as promoieties to selected anti-inflammatory drugs. The prodrug uptake in OATP1C1-expressing human U-87MG glioma cells demonstrated higher accumulation with T₄ promoiety compared to those with DIT promoiety or the parent drugs themselves. In silico models of OATP1C1 suggested dynamic binding for the prodrugs, wherein the pose changed from vertical to horizontal. The predicted binding energies correlated with the transport profiles, with T₄ derivatives exhibiting higher binding energies when compared to prodrugs with a DIT promoiety. Interestingly, the prodrugs also showed utilization of oatp1a4/1a5/1a6 in mouse primary astrocytes, which was further supported by docking studies and a great potential for improved brain drug delivery.

中文翻译：

利用 L-甲状腺素衍生的前药通过有机阴离子转运多肽 1C1 (OATP1C1) 靶向神经胶质细胞

OATP1C1（有机阴离子转运多肽 1C1）将甲状腺激素，特别是甲状腺素 (T ₄ ) 转运到人星形胶质细胞中。在这项研究中，我们研究了利用 OATP1C1 改善抗炎药物向神经胶质细胞的输送的潜力。我们通过将 T ₄和 3,5-二碘-L-酪氨酸 (DIT) 作为前体部分掺入选定的抗炎药物中，设计并合成了八种新型前药。与具有 DIT 前体或母体药物本身的那些相比，表达 OATP1C1 的人 U-87MG 神经胶质瘤细胞中 T ₄前体部分的前药摄取表现出更高的积累。 OATP1C1 的计算机模型表明前药的动态结合，其中姿势从垂直变为水平。预测的结合能与转运谱相关，与具有 DIT 前体部分的前药相比，T ₄衍生物表现出更高的结合能。有趣的是，这些前药还显示在小鼠原代星形胶质细胞中利用了 oatp1a4/1a5/1a6，这得到了对接研究的进一步支持，并且具有改善大脑药物递送的巨大潜力。

更新日期：2023-11-06

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