Conformationally-restricted amino acid analogues bearing a distal sulfonic acid show selective inhibition of system xc- over the vesicular glutamate transporter

A panel of amino acid analogs and conformationally-restricted amino acids bearing a sulfonic acid were synthesized and tested for their ability to preferentially inhibit the obligate cysteine–glutamate transporter system xc- versus the vesicular glutamate transporter (VGLUT). Several promising candidate molecules were identified: R/S  -4-[4′-carboxyphenyl]-phenylglycine, a biphenyl substituted analog of 4-carboxyphenylglycine and 2-thiopheneglycine-5-sulfonic acid both of which reduced glutamate uptake at system xc- by 70–75% while having modest to no effect on glutamate uptake at VGLUT.

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