How to rescue misfolded SERT, DAT and NET: targeting conformational intermediates with atypical inhibitors and partial releasers.

摘要: Point mutations in the coding sequence for solute carrier 6 (SLC6) family members result clinically relevant disorders, which are often accounted by a loss-of-function phenotype. In many instances, mutated transporter is not delivered to cell surface because it retained endoplasmic reticulum (ER). The underlying defect improper folding of and case known dopamine mutants. monoamine transporters, i.e. transporters norepinephrine (NET/SLC6A2), (DAT/SLC6A3) serotonin (SERT/SLC6A4), have rich pharmacology; hence, their folding-deficient mutants lend themselves explore concept pharmacological chaperoning. Pharmacochaperones small molecules, bind intermediates with exquisite specificity scaffold them folded state, exported from ER surface. Pharmacochaperoning mutant however, straightforward: ionic conditions within conducive binding most typical ligands. A collection compounds exists, classified as atypical ligands they trap unique conformational states. mode some DAT inhibitors has been linked anti-addictive action. Here, we propose that also recently partial releasers can serve pharmacochaperones.