title: Challenging the catechism of therapeutics for chronic neuropathic pain: Targeting CaV2.2 interactions with CRMP2 peptides.
abstract: Chronic neuropathic pain management is a worldwide concern. Pharmaceutical companies globally have historically targeted ion channels as the therapeutic catechism with many blockbuster successes. Remarkably, no new pain therapeutic has been approved by European or American regulatory agencies over the last decade. This article will provide an overview of an alternative approach to ion channel drug discovery: targeting regulators of ion channels, specifically focusing on voltage-gated calcium channels. We will highlight the discovery of an anti-nociceptive peptide derived from a novel calcium channel interacting partner - the collapsin response mediator protein 2 (CRMP2). In vivo administration of this peptide reduces pain behavior in a number of models of neuropathic pain without affecting sympathetic-associated cardiovascular activity, memory retrieval, sensorimotor function, or depression. A CRMP2-derived peptide analgesic, with restricted access to the CNS, represents a completely novel approach to the treatment of severe pain with an improved safety profile. As peptides now represent one of the fastest growing classes of new drugs, it is expected that peptide targeting of protein interactions within the calcium channel complex may be a paradigm shift in ion channel drug discovery.
authors.affiliation: Sophia Therapeutics LLC, 351 West 10th Street, Indianapolis, IN 46202, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: Feldman
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000378:metabolism*; D002908:Chronic Disease; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use; D015398:Signal Transduction
chemical_list: D000700:Analgesics; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; C095114:collapsin response mediator protein-2
keywords: Anti-nociceptive; BBB; CBD; CGRP; CNS; CPP; CRMP2; CTX; Ca(2+) channel binding domain; CaV2.2; Calcium channels; DIV; DRG; HIV-1 transactivator of transcription domain; LPC; N-type voltage-gated Ca(2+) channel; NRTI; Neuropathic pain; PWT; Peptide; R9; ST; Sophia Therapeutics; TAT; TNI; blood brain barrier; calcitonin gene related peptide; cell penetrating peptide; central nervous system; collapsin response mediator protein 2; conotoxin; days in vitro; dorsal root ganglion; lysophosphotidylcholine; nona-arginine; nucleoside reverse transcriptase inhibitor; omega-conotoxin; paw withdrawal threshold; sEPSCs; spontaneous excitatory postsynaptic currents; tibial nerve injury; ω-CTX