Tropane-Based Ibogaine Analog Rescues Folding-Deficient Serotonin and Dopamine Transporters.
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
ACS pharmacology & translational science April 9, 2021 DOI: 10.1021/acsptsci.0c00102 via PubMed
Summary
AI-generated from the abstractProtein 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.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Drosophila harboring the DAT-PG584,585AA mutation and human DAT mutant proteins in vitro |
| Interventions | ibogaine noribogaine |
| Keywords | Protein misfolding Protein folding diseases Proteinopathy Proteostasis Conformational diseases |
| Citations | 37 |
| Key finding | A tropane-based ibogaine analog (9b) rescued 6 out of 13 disease-associated human DAT mutant proteins in vitro and acted as an effective pharmacochaperone in vivo in Drosophila. |
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 mutant proteins, 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, as well as for rescuing two equivalent synthetic folding-deficient mutants, SERT-PG601,602AA and DAT-PG584,585AA. The most active tropane-based analog (9b) was also an effective pharmacochaperone in vivo in Drosophila harboring the DAT-PG584,585AA mutation and rescued 6 out of 13 disease-associated human DAT mutant proteins in vitro. Hence, a novel lead pharmacochaperone has been identified that demonstrates medication development potential for patients harboring DAT mutations.