Protein misfolding caused by missense mutations is rare but collectively leads to serious folding diseases. Ibogaine and noribogaine can correct folding defects in the dopamine transporter (DAT) but rescue only a limited number of DAT mutants linked to infantile Parkinsonism and dystonia. By reconfiguring the ibogaine ring system, a series of analogs were generated and tested for binding to wild-type transporters and for rescuing two synthetic folding-deficient mutants. The most active tropane-based analog (9b) acted as an effective pharmacochaperone in vivo in Drosophila carrying a DAT mutation and rescued 6 out of 13 disease-associated human DAT mutant proteins in vitro, identifying a novel lead compound with potential for medication development for patients with DAT mutations.
A novel tropane-based compound, 9b, corrects folding defects in the dopamine transporter (DAT) caused by specific mutations linked to infantile Parkinsonism and dystonia. By reconfiguring the ibogaine ring system, researchers created analogs that bind to wild-type transporters and rescue two synthetic folding-deficient mutants, SERT-PG 601,602 AA and DAT-PG 584,585 AA. The most active analog, 9b, was effective as a pharmacochaperone in fruit flies carrying the DAT-PG 584,585 AA mutation and rescued six out of 13 disease-associated human DAT mutants in cell-based tests. This compound represents a promising lead for developing medications for patients with DAT mutations.