Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B0AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases

Aditya Yadav,Qi Cheng,Stefan Bröer,Indrapal Singh Aidhen,Praveen Kumar Tiwari,Nishank Shah,Kiran Javed

doi:10.3389/fphar.2020.00140

Abstract

Lack of B0AT1 (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 B0AT1 by medicinal chemistry and identified second generation inhibitors by high through-put screening. Modified diarylmethine compounds inhibited B0AT1 with IC50 values ranging from 8–90 μM. A second generation of inhibitors was derived from high-throughput screening and showed higher affinity (IC50 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 B0AT1 substrates, but were likely to bind in the vicinity of the substrate binding site.

Highlights

Transport of amino acids by epithelial cells of the intestine and kidney plays an important role in organismic amino acid homeostasis (Cynober, 2002; Broer and Broer, 2017)
Most SLC6A19ko animals showed a significant protection against non-alcoholic steatohepatitis (NASH), suggesting a potential of B0AT1 inhibitors to treat this metabolic disorder
Due to the workflow of the FLIPR assay compounds are pre-incubated for 30 min with the cells, which can result in lower IC50-values (e.g. Table 1)

Summary

Introduction

Transport of amino acids by epithelial cells of the intestine and kidney plays an important role in organismic amino acid homeostasis (Cynober, 2002; Broer and Broer, 2017). The epithelial neutral amino acid transporter B0AT1 (SLC6A19) was initially identified as the molecule mutated in the rare condition Hartnup disorder (Kleta et al, 2004; Seow et al, 2004). B0AT1 is expressed in the apical membrane of intestinal and renal epithelial cells (Kleta et al, 2004; Broer et al, 2011). Mutations of B0AT1 cause intestinal malabsorption and renal aminoaciduria. Renal aminoaciduria is restricted to neutral amino acids and defines the disorder in Abbreviations: HBSS, Hank’s balanced salt solution; HTS, High through put screening; NASH, non-alcoholic steatohepatitis; PKU, phenylketonuria

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Results

Conclusion