Yadav Aditya, Shah Nishank, Tiwari Praveen Kumar, Javed Kiran, Cheng Qi, Aidhen Indrapal Singh, Bröer Stefan
Research School of Biology, Australian National University, Canberra, ACT, Australia.
Department of Chemistry, Indian Institute of Technology Madras, Chennai, India.
Front Pharmacol. 2020 Feb 28;11:140. doi: 10.3389/fphar.2020.00140. eCollection 2020.
Lack of BAT1 (SLC6A19) partially protects mice against the onset of non-alcoholic steatohepatitis (NASH). To achieve a similar outcome through pharmacological treatment, we improved previously identified inhibitors of BAT1 by medicinal chemistry and identified second generation inhibitors by high through-put screening. Modified diarylmethine compounds inhibited BAT1 with IC values ranging from 8-90 μM. A second generation of inhibitors was derived from high-throughput screening and showed higher affinity (IC of 1-15 μM) and strong selectivity against amino acid transporters with similar substrate specificity, such as ASCT2 (SLC1A5) and LAT1 (SLC7A5). All compounds were unrelated to BAT1 substrates, but were likely to bind in the vicinity of the substrate binding site.
缺乏BAT1（SLC6A19）可部分保护小鼠免受非酒精性脂肪性肝炎（NASH）的发病影响。为了通过药物治疗实现类似的结果，我们通过药物化学改进了先前鉴定出的BAT1抑制剂，并通过高通量筛选鉴定出第二代抑制剂。修饰后的二芳基甲烷化合物抑制BAT1的IC值范围为8 - 90μM。第二代抑制剂来自高通量筛选，显示出更高的亲和力（IC为1 - 15μM），并且对具有相似底物特异性的氨基酸转运蛋白具有很强的选择性，如ASCT2（SLC1A5）和LAT1（SLC7A5）。所有化合物均与BAT1底物无关，但可能结合在底物结合位点附近。
