Bhat Shreyas, Guthrie Daryl A, Kasture Ameya, El-Kasaby Ali, Cao Jianjing, Bonifazi Alessandro, Ku Therese, Giancola JoLynn B, Hummel Thomas, Freissmuth Michael, Newman Amy Hauck
Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Waehringerstrasse 13a, Vienna 1090, Austria.
Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, United States.
ACS Pharmacol Transl Sci. 2020 Aug 28;4(2):503-516. doi: 10.1021/acsptsci.0c00102. eCollection 2021 Apr 9.
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-PGAA and DAT-PGAA. The most active tropane-based analog () was also an effective pharmacochaperone in harboring the DAT-PGAA mutation and rescued 6 out of 13 disease-associated human DAT mutant proteins . Hence, a novel lead pharmacochaperone has been identified that demonstrates medication development potential for patients harboring DAT mutations.
导致蛋白质错误折叠的错义突变很少见，但总体而言，有缺陷的蛋白质折叠疾病后果严重。折叠缺陷适合进行药理学纠正（药物伴侣疗法），但其潜在机制仍然不明。伊博格碱及其活性代谢物去甲伊博格碱可纠正多巴胺转运体（DAT）的折叠缺陷，但它们只能挽救极少数导致婴儿帕金森病和肌张力障碍的折叠缺陷DAT突变蛋白。在此，通过重新构建复杂的伊博格碱环系统并探索与野生型转运体结合以及挽救两个等效的合成折叠缺陷突变体SERT-PGAA和DAT-PGAA的结构要求，生成了一系列类似物。活性最高的基于托烷的类似物（）在携带DAT-PGAA突变方面也是一种有效的药物伴侣，并挽救了13种与疾病相关的人类DAT突变蛋白中的6种。因此，已鉴定出一种新型先导药物伴侣，它显示出对携带DAT突变患者的药物开发潜力。
