title: 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.
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)].
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacology and Toxicology, 950 West Walnut Street, Indianapolis, IN 46202, USA.
authors: Andrew D
authors: AD
authors: Piekarz
authors: Michael R
authors: MR
authors: Due
authors: May
authors: M
authors: Khanna
authors: Bo
authors: B
authors: Wang
authors: Matthew S
authors: MS
authors: Ripsch
authors: Ruizhong
authors: R
authors: Wang
authors: Samy O
authors: SO
authors: Meroueh
authors: Michael R
authors: MR
authors: Vasko
authors: Fletcher A
authors: FA
authors: White
authors: Rajesh
authors: R
authors: Khanna
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000628:therapy*; D000595:Amino Acid Sequence; D000818:Animals; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D002469:Cell Separation; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D059225:Nociception / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000209:etiology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D020864:Calcium Channels, N-Type; D036341:Intercellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D010455:Peptides; C095114:collapsin response mediator protein-2; D054322:tat Gene Products, Human Immunodeficiency Virus