| Background: Thyroxine derivatives are investigated as a possible treatment for Allan-Herndon-Dudley syndrome, a syndrome arising from inherited X-linked recessive mutations in thyroid hormone transporter MCT8. The overlapping substrate preference of MCT8 and OATP1C1 suggests that therapeutic targeting of OATP1C1 may be a viable option for T3/thyroid hormone replacement. Objective: We measured the substrate preference/hierarchy for thyroxine derivatives, which competitively inhibit the transport of thyroxine, and determined Ki values for each compound. Results: Molecular characteristics essential for thyroxine recognition and transport by Oatp1c1 include the highly polarizable outer ring iodides located at the 3' position, 5' position, and the negatively charged carboxyl group. The positively charged amine group appears to be deleterious to the substrate-protein interaction of thyroxine, as evidenced by increased affinity for the thyroxine derivative molecule upon removal. The volume and hydrophobicity of the two ring system of thyroxine also contributes significantly to substrate affinity. Conclusions: Identifying the essential substrate elements necessary for Oatp1c1 thyroxine recognition is required for the full biochemical characterization of the Oatp1c1 substrate channel. This work will facilitate the selection of drug like molecules targeting Oatp1c1 expressing cells of the central nervous system and specifically novel therapeutic thyroxine derivatives. |
