Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Poster Abstracts

27-POS Board 7 IDENTIFICATION OF CONFORMATIONALLY-BIASED PHARMACOLOGICAL CHAPERONES FOR SLC6A8 CREATINE TRANSPORTER DEFICIENCY SYNDROME Jacklyn Gallagher 1 ; Charles Kuntz 1 ; Wesley Penn 2 ; Jonathan Schlebach 1 ; 1 Purdue University, Chemistry, West Lafayette, IN, USA 2 Indiana University, Bloomington, Chemistry, Bloomington, IN, USA Creatine uptake by the SLC6A8 creatine transporter protein (CT1) is critical for energy homeostasis in the central nervous system. Over one hundred loss-of-function (LOF) mutations in the SLC6A8 gene are known to cause creatine transporter deficiency syndrome (CTD)- a spectrum of X-linked neurological disorders associated with intellectual disability, autism, and epilepsy. These incurable disorders fundamentally arise from a loss of CT1 expression and/ or activity, which results in insufficient creatine uptake within the brain. Most CTD mutations appear to promote CT1 misfolding. The misfolding of related SLC6 transporters can be corrected by atypical inhibitors that selectively bind to the inward-facing conformation of the transporter protein. To identify small molecules that correct this primary defect in CTD, we constructed structural homology models of CT1 in each of its conformational states and carried out a virtual screen for conformationally-biased ligands selectively stabilize its inward-facing state. An experimental characterization of our top hits has identified several compounds that enhance the plasma membrane expression CT1. Our most potent pharmacochaperones appear to bind within the substrate binding site and to make extensive contact within creatine’s intracellular permeation pathway. These compounds represent promising candidates for the development of pharmacological chaperones for CTD.


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