CRMP-2 peptide mediated decrease of high and low voltage-activated calcium channels, attenuation of nociceptor excitability, and anti-nociception in a model of AIDS therapy-induced painful peripheral neuropathy

Molecular Pain

Rajesh Khanna¹  Fletcher A White⁶  Michael R Vasko⁶  Samy O Meroueh⁵  Ruizhong Wang²  Matthew S Ripsch³  Bo Wang⁵  May Khanna⁴  Michael R Due⁴  Andrew D Piekarz² 

[1] Sophia Therapeutics LLC, 351 West 10th Street, Indianapolis, IN, 46202, USA;Department of Pharmacology and Toxicology, 950 West Walnut Street, Indianapolis, IN, 46202, USA;Department of Anesthesia, 950 West Walnut Street, Indianapolis, IN, 46202, USA;Department of Biochemistry and Molecular Biology, Health Information and Translational Sciences Building, 410 W. 10th Street, HS 5000, Indianapolis, IN, 46202, USA;Department of Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Health Information and Translational Sciences Building, 410 W. 10th Street, HS 5000, Indianapolis, IN, 46202, USA;Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, 950 West Walnut Street, Indianapolis, IN, 46202, USA

关键词: Molecular dynamics;    Calcium channels;    AIDS therapy-induced chronic pain;    Nociception;    Excitability;    Peptide;   

Others  :  863803
DOI  :  10.1186/1744-8069-8-54

 received in 2012-04-09, accepted in 2012-07-02,  发布年份 2012

【 摘 要 】

Background

The ubiquity of protein-protein interactions in biological signaling offers ample opportunities for therapeutic intervention. We previously identified a peptide, designated CBD3, that suppressed inflammatory and neuropathic behavioral hypersensitivity in rodents by inhibiting the ability of collapsin response mediator protein 2 (CRMP-2) to bind to N-type voltage-activated calcium channels (CaV2.2) [Brittain et al. Nature Medicine 17:822–829 (2011)].

Results and discussion

Here, we utilized SPOTScan analysis to identify an optimized variation of the CBD3 peptide (CBD3A6K) that bound with greater affinity to Ca²⁺ channels. Molecular dynamics simulations demonstrated that the CBD3A6K peptide was more stable and less prone to the unfolding observed with the parent CBD3 peptide. This mutant peptide, conjugated to the cell penetrating motif of the HIV transduction domain protein TAT, exhibited greater anti-nociception in a rodent model of AIDS therapy-induced peripheral neuropathy when compared to the parent TAT-CBD3 peptide. Remarkably, intraperitoneal administration of TAT-CBD3A6K produced none of the minor side effects (i.e. tail kinking, body contortion) observed with the parent peptide. Interestingly, excitability of dissociated small diameter sensory neurons isolated from rats was also reduced by TAT-CBD3A6K peptide suggesting that suppression of excitability may be due to inhibition of T- and R-type Ca²⁺ channels. TAT-CBD3A6K had no effect on depolarization-evoked calcitonin gene related peptide (CGRP) release compared to vehicle control.

Conclusions

Collectively, these results establish TAT-CBD3A6K as a peptide therapeutic with greater efficacy in an AIDS therapy-induced model of peripheral neuropathy than its parent peptide, TAT-CBD3. Structural modifications of the CBD3 scaffold peptide may result in peptides with selectivity against a particular subset of voltage-gated calcium channels resulting in a multipharmacology of action on the target.

【 授权许可】

   
2012 Piekarz et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

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