Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity
Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity
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DOI：
10.1038/s41401-021-00793-3
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发表时间：
2021-12
影响因子：
8.2
通讯作者：
Dong Huang;Ying-yuan Zhao;Rui-min Wang;Wei Li;Fang-yu Yuan;Xue-long Yan;Xiao Yang;G. Tang-
中科院分区：
文献类型：
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作者：
Dong Huang;Ying-yuan Zhao;Rui-min Wang;Wei Li;Fang-yu Yuan;Xue-long Yan;Xiao Yang;G. Tang-
胆汁淤积是一系列胆汁流动障碍相关肝病的主要原因。孕烷X受体（Pregnane X receptor，PXR）是内源性和外源性生物代谢的重要调节因子，被认为是胆汁淤积症治疗的一个重要靶点。在这项研究中，我们进行了人类PXR（hPXR）激动剂筛选使用双荧光素酶报告基因分析，这导致发现了一系列有效的hPXR激动剂从一个smallEuphorbiaceaediterpenoid库，包含35个结构不同的二萜类化合物与8个不同的骨架类型。活性最高的化合物6是一种lathyrane二萜类化合物（5/11/3环系统），具有剂量依赖性地高选择性激活hPXR，并显著上调hPXR下游基因CYP 3A 4和UGT 1A 1的表达。在LCA诱导的胆汁淤积小鼠模型中，化合物6（50 mg· kg-1. d-1，ip）给药7天显著抑制肝坏死，降低血清AST、ALT、Tbili、ALP和TBA水平，改善LCA诱导的胆汁淤积性肝损伤。化合物6通过激活PXR通路，加速毒性BA的解毒，促进肝再生，发挥抗胆汁淤积的作用。这些结果表明，lathyrane二萜类化合物可能作为一个有前途的支架抗胆汁淤积药物的未来发展。
Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a smallEuphorbiaceaediterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genesCYP3A4andUGT1A1. In LCA-induced cholestasis mouse model, administration of compound6(50 mg· kg−1. d−1, ip) for 7 days significantly suppressed liver necrosis and decreased serum levels of AST, ALT, Tbili, ALP, and TBA, ameliorating LCA-induced cholestatic liver injury. We further revealed that compound6exerted its anti-cholestatic efficacy via activation of PXR pathway, accelerating the detoxification of toxic BAs and promoting liver regeneration. These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs.