Investigation of compounds which inhibit the sodium-dependent neutral amino acid transporter B0AT1 (SLC6A19)

Abstract

The SLC6A19 gene encodes the Broad Neutral Amino Acid Transporter 1 (B0AT1), a crucial protein for the cellular uptake of neutral amino acids in the brush-border membranes of the kidneys and small intestine. Defective B0AT1 function leads to Hartnup disorder, an autosomal recessive metabolic disease characterized by diverse clinical manifestations, including dermal, neurological, and psychiatric symptoms. Conversely, pharmacological inhibition of B0AT1 holds significant therapeutic potential for a range of other metabolic diseases. For instance, selective B0AT1 inhibition could reduce the intestinal absorption of phenylalanine in patients with phenylketonuria (PKU), thereby mitigating the accumulation of this neurotoxic amino acid. This approach also presents a novel therapeutic strategy for managing type II diabetes by delaying post-meal glucose absorption.

Building upon the identification of a previously reported (by collaborators in the Broer group) cinromide-like compound as a potent B0AT1 inhibitor, this study reports the systematic synthesis and biological evaluation of a series of novel analogues to elucidate their structure-activity relationship (SAR). Through meticulous chemical modifications of the lead compound, we aimed to define the molecular features critical for B0AT1 inhibition. The SAR was established through a combination of in vitro functional assays, which quantified the inhibitory activity of each analogue, and computational docking studies performed in collaboration with a research team specializing in molecular modeling (Yan group). The insights gained from this research provide a rational basis for the design of more potent and selective B0AT1 inhibitors with enhanced pharmacological properties. Show more