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
- Equal contributors
1 Department of Pharmacology and Toxicology, 950 West Walnut Street, Indianapolis, IN, 46202, USA
2 Department of Anesthesia, 950 West Walnut Street, Indianapolis, IN, 46202, USA
3 Department of Biochemistry and Molecular Biology, Health Information and Translational Sciences Building, 410 W. 10th Street, HS 5000, Indianapolis, IN, 46202, USA
4 Department of Chemistry, Health Information and Translational Sciences Building, 410 W. 10th Street, HS 5000, Indianapolis, IN, 46202, USA
5 Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, 950 West Walnut Street, Indianapolis, IN, 46202, USA
6 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
7 Sophia Therapeutics LLC, 351 West 10th Street, Indianapolis, IN, 46202, USA
Molecular Pain 2012, 8:54 doi:10.1186/1744-8069-8-54Published: 24 July 2012
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.
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.