Probing the Substrate Binding Site of SNAT2 With Amino Acid Analogues: A Structure-Activity Relationship Study

Research output: Contribution to conference without publisher/journalPosterResearch


The sodium-coupled neutral amino acid transporter SNAT2 (SLC38A2) has been implicated to play a role in cancers such as prostate cancer through its transport of e.g., glutamine and sarcosine. However, few selective inhibitors have been found for the transporter and little is known about the structural requirements for SNAT2 ligand binding. In this study the aim was to establish the basic structure-activity relationship for SNAT2 using derivatives of amino acids. These amino acid analogues were studied for their ability to inhibit SNAT2 mediated 3H-glycine uptake in hyperosmotic treated PC-3 cells. Hyperosmotic cell culture has previously been shown to upregulate SNAT2 transport activity. The analogues either contain small modifications at the C-terminus, N-terminus or in the side chain residue. Furthermore, a FLIPR membrane potential assay (FMP) was used to distinguish substrates from true inhibitors. The results showed that ester derivatives of the C-terminus maintained SNAT2 affinity, suggesting that the negative charge was less important. On the other hand, the positive charge on the nitrogen appeared to be more important as analogues without this charge lost SNAT2 affinity. The side chain residue can be elongated relative to natural amino acid but preferably linear, as branching tended to decrease affinity. Introduction of terminal benzyl groups to the side chain appeared to be favorable for binding while potentially being a way of turning substrates into true inhibitors. SNAT2 prefers L-configured amino acids but also recognize D-amino acids to some degree. Thus, this study provides valuable insights for the development of SNAT2 inhibitors.
Original languageEnglish
Publication date27. Sept 2023
Publication statusPublished - 27. Sept 2023
EventRESOLUTE Conference: Unlocking Transporters for Drug Discovery - Wien, Austria
Duration: 27. Sept 202329. Sept 2023


ConferenceRESOLUTE Conference
Internet address


  • SNAT2
  • amino acid transporter
  • amino acid analog
  • Structure-Activity Relationship
  • PC-3 cells


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