Small organic molecule disruptors of Cav3.2 - USP5 interactions reverse inflammatory and neuropathic pain

Molecular Pain

Gerald W Zamponi²  Tom A Pfeifer¹  Lina Chen²  Clare M Gladding¹  N Daniel Berger²  Agustin Garcia Caballero²  Vinicius M Gadotti² 

[1] Centre for Drug Research and Development, 2405 Wesbrook Mall – 4th Floor, Vancouver V6T 1Z3, BC, Canada;Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, Calgary T2N 4N1, NW, Canada

关键词: Gossypetin;    Suramin;    Chronic pain;    USP5;    T-type channels;   

Others  :  1159801
DOI  :  10.1186/s12990-015-0011-8

 received in 2015-01-02, accepted in 2015-03-02,  发布年份 2015

【 摘 要 】

Background

Cav3.2 channels facilitate nociceptive transmission and are upregulated in DRG neurons in response to nerve injury or peripheral inflammation. We reported that this enhancement of Cav3.2 currents in afferent neurons is mediated by deubiquitination of the channels by the deubiquitinase USP5, and that disrupting USP5/Cav3.2 channel interactions protected from inflammatory and neuropathic pain.

Results

Here we describe the development of a small molecule screening assay for USP5-Cav3.2 disruptors, and report on two hits of a ~5000 compound screen - suramin and the flavonoid gossypetin. In mouse models of inflammatory pain and neuropathic pain, both suramin and gossypetin produced dose-dependent and long-lasting mechanical anti-hyperalgesia that was abolished or greatly attenuated in Cav3.2 null mice. Suramin and Cav3.2/USP5 Tat-disruptor peptides were also tested in models of diabetic neuropathy and visceral pain, and provided remarkable protection.

Conclusions

Overall, our findings provide proof of concept for a new class of analgesics that target T-type channel deubiquitination.

【 授权许可】

   
2015 Gadotti et al.; licensee BioMed Central.

【 图 表 】

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