A tropane-based ibogaine analog rescues folding-deficient SERT and DAT
Shreyas Bhat, Daryl A. Guthrie, Ameya Kasture, Ali El-Kasaby, Jianjing Cao, Alessandro Bonifazi, Therese Ku, Jolynn B. Giancola, Thomas Hummel, Michael Freissmuth, Amy Hauck Newman
bioRxiv (Cold Spring Harbor Laboratory) July 14, 2020 preprint DOI: 10.1101/2020.07.14.202325 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study |
|---|---|
| Population | Drosophila (fruit flies) and cultured human cells |
| Interventions | ibogaine noribogaine |
| Topics | Ibogaine |
| Keywords | Tropane Dopamine transporter Mutant Cell biology Biochemistry Stereochemistry Gene |
| Citations | 3 |
| Key points | A tropane-based analog (9b) rescues folding defects in multiple DAT mutants, including six of 13 disease-associated human variants, and shows in vivo efficacy in Drosophila. |
Abstract
Abstract Missense mutations that give rise to protein misfolding are rare, but collectively, defective protein folding diseases are consequential. Folding deficiencies are amenable to pharmacological correction (pharmacochaperoning), but the underlying mechanisms remain enigmatic. Ibogaine and its active metabolite noribogaine correct folding defects in the dopamine transporter (DAT), but they rescue only a very limited number of folding-deficient DAT mutants, which give rise to infantile Parkinsonism and dystonia. Herein, a series of analogs was generated by reconfiguring the complex ibogaine ring system and exploring the structural requirements for binding to wild type transporters, and for rescuing two equivalent synthetic folding-deficient mutants, SERT-PG 601,602 AA and DAT-PG 584,585 AA. The most active tropane-based analog ( 9b ) was also an effective pharmacochaperone in vivo , in Drosophila harboring DAT-PG 584,585 AA and rescued six out of 13 disease-associated human DAT mutants in vitro. Hence, a novel lead pharmacochaperone has been identified that demonstrates medication development potential for patients harboring DAT mutants.