Figure 3.

A molecular view of CTD and the putative therapeutic approaches. CTD mutations trigger folding deficits or impair CRT1 substrate uptake activity (both resulting in the lack of functional CRT1 proteins at the cell surface; top right). Three approaches can be used to restore creatine supply in the cells: (1) conjugating creatine with salts, taken up by other transporters; and (2) creating lipophilic creatine analogs, to establish transporter-independent delivery of cyclocreatine, creatine benzyl, and fatty acid esters (top left), or (3) pharmacochaperoning to correct folding defects in CRT1 variants (recovering surface expression and creatine uptake activity of CTD mutant protein, top middle) by treatment with small molecules, that act either directly on the CRT1 itself (i.e., transporter ligands) or manipulate the cellular folding machinery (e.g., heat shock protein inhibitors and chemical chaperones).