Research

Molecular Pain

, 8:54

Open Access This content is freely available online to anyone, anywhere at any time.

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

  • Andrew D PiekarzAffiliated withDepartment of Pharmacology and Toxicology Email author 
  • , Michael R DueAffiliated withDepartment of Biochemistry and Molecular Biology, Health Information and Translational Sciences Building Email author 
  • , May KhannaAffiliated withDepartment of Biochemistry and Molecular Biology, Health Information and Translational Sciences Building
  • , Bo WangAffiliated withDepartment of Biochemistry and Molecular Biology, Health Information and Translational Sciences BuildingDepartment of Chemistry, Health Information and Translational Sciences BuildingDepartment of Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Health Information and Translational Sciences Building
  • , Matthew S RipschAffiliated withDepartment of Anesthesia
  • , Ruizhong WangAffiliated withDepartment of Pharmacology and Toxicology
  • , Samy O MerouehAffiliated withDepartment of Biochemistry and Molecular Biology, Health Information and Translational Sciences BuildingDepartment of Chemistry, Health Information and Translational Sciences BuildingProgram in Medical Neurosciences, Paul and Carole Stark Neurosciences Research InstituteDepartment of Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Health Information and Translational Sciences Building
  • , Michael R VaskoAffiliated withDepartment of Pharmacology and ToxicologyProgram in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute
  • , Fletcher A WhiteAffiliated withDepartment of AnesthesiaProgram in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute
    • , Rajesh KhannaAffiliated withDepartment of Pharmacology and ToxicologyProgram in Medical Neurosciences, Paul and Carole Stark Neurosciences Research InstituteSophia Therapeutics LLC Email author 

Abstract

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.

Keywords

Peptide Excitability Nociception AIDS therapy-induced chronic pain Calcium channels Molecular dynamics