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A peptide uncoupling CRMP-2 from the presynaptic Ca2+ channel complex demonstrates efficacy in animal models of migraine and AIDS therapy-induced neuropathy

1Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA

2Department of Anesthesia, Indiana University School of Medicine, Indianapolis, USA

3Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, USA

4Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, USA

5Sophia Therapeutics LLC, 351 West 10th Street, Indianapolis, Indiana, 46202, USA

© 2012 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. (CC BY-NC-ND 3.0)

Citation Information: Translational Neuroscience. Volume 3, Issue 1, Pages 1–8, ISSN (Online) 2081-6936, ISSN (Print) 2081-3856, DOI: 10.2478/s13380-012-0002-4, March 2012

Publication History

Published Online:


Biological, genetic, and clinical data provide compelling proof for N-type voltage-gated calcium channels (CaV2.2) as therapeutic targets for chronic pain. While decreasing channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse effects. Targeting regulators of channel activity may facilitate improved analgesic properties associated with channel block and afford a broader therapeutic window. Towards this end, we recently identified a short peptide, designated CBD3, derived from collapsin response mediator protein 2 (CRMP-2) that suppressed inflammatory and neuropathic hypersensitivity by inhibiting CRMP-2 binding to CaV2.2 [Brittain et al., Nature Medicine 17:822–829 (2011)]. Rodents administered CBD3 intraperitoneally, fused to the HIV TAT protein cell penetrating domain, exhibited antinociception lasting ∼4 hours highlighting potential instability, limited oral bioavailability, and/or rapid elimination of peptide. This report focuses on improving upon the parental CBD3 peptide. Using SPOTScan analysis of synthetic versions of the parental CBD3 peptide, we identified peptides harboring single amino acid mutations that bound with greater affinity to CaV2.2. One such peptide, harboring a phenylalanine instead of glycine (G14F), was tested in rodent models of migraine and neuropathic pain. In vivo laser Doppler blood flowmetry measure of capsaicin-induced meningeal vascular responses related to headache pain was almost completely suppressed by dural application of the G14F peptide. The G14F mutant peptide, administered intraperitoneally, also exhibited greater antinociception in Stavudine (2′-3′-didehydro-2′-3′-dideoxythymidine (d4T)/Zerit®) model of AIDS therapy-induced peripheral neuropathy compared to the parent CBD3 peptide. These results demonstrate the patent translational value of small biologic drugs targeting CaV2.2 for management of clinical pain.

Keywords: N-type calcium channel; CRMP-2; Uncoupling peptide; Meningeal blood flow; Migraine model; d4T/Zerit/Stavudine; NTR; AIDS therapy-induced neuropathic pain; Chronic pain

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