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.

Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties

“…In our opinion, difference in net charge should have the effect of increasing neuroprotective potency (Meloni et al, 2015). The importance of cationic charge and the presence of arginine residues in TAT-CDB3 peptide is further highlighted by evidence of increased efficacy with respect to inhibition of evoked calcium influx and pain suppression following substitution of an alanine by a lysine residue (TAT-CBD3-A6K: +12) and replacement of TAT with R9 (R9-CDB3: +12) (Feldman & Khanna, 2013). The A6K modification results in increased binding affinity of CDB3:A6K Cav2.2, while replacement of TAT with R9 improves peptide cell transduction.…”

“…There are several lines of evidence based on our findings and those of others that support our endocytosis hypothesis. Arginine-rich peptides, including so called "neuroprotective peptides" fused to TAT have been shown to: i) reduce neuronal calcium influx (Meloni et al, 2015) and interfere with ion channel function (NMDA receptor: Ferrer-Montiel et al, 1988;Tu et al, 2010;Sinai et al, 2010;Brittain et al, 2011b;Brustovetsky et al, 2014, VR1: Planells-Cases et al, 2000, CaV2.2: Brittain et al, 2011a, 2011bFeldman & Khanna, 2013;Brustovetsky et al, 2014;sodium calcium exchanger [NCX], CaV3.3: García-Caballero et al, 2014); ii) cause internalisation of neuronal ion channels (Brustovetsky et al, 2014;Sinai et al, 2010); and iii) require endocytosis as a prerequisite for neuroprotection (Meloni et al, 2015;Vaslin et al, 2011). Interestingly, other TAT-fused peptides have also been shown to interfere with the function of neuronal receptors (D1R-D2R; Pei et al, 2010;PTPσ: Lang et al, 2015).…”

“…Replacing the TAT peptide with poly-arginine-9 (R9) produced an even greater effect than for TAT-CBD and TAT-CBD3A6K in terms of inhibition of neuronal calcium influx and neuropathic pain (Feldman & Khanna, 2013;Ju et al, 2013).…”

Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

“…78,79 In contrast to the inhibitory action of pregabalin, collapsin response mediator protein 2 (CRMP-2) was reported to bind to HVA N-type calcium channels (Cav2.2) resulting in increased surface expression as well as calcium currents in hippocampal and sensory neurons. [80][81][82][83] Further work established the notion that CRMP-2 expression levels allow the control of Cav2.2 function, nociceptor excitability and transmitter release. 80,83 These findings prompted the mapping of the mutual binding sites of CRMP-2 and Cav2.2 with the goal to uncouple their physical interaction and thereby antagonize CRMP-2-mediated Cav2.2 hyperactivity.…”

Current and Future Issues in the development of spinal agents for the management of pain

“…Considerable work has focused on the development of other conopeptides as well as small molecules [160,167]. Alternatively, there is considerable interest in altering N-type VSCC function by impeding its membrane trafficking and such strategies have been shown to alter nociceptive processing [168]; ii) VSCCs are broadly divided into two types: high-voltage-activated (HVA) and low-voltage-activated (LVA) channels. HVA channels are further divided into L-, P/Q-, N-and R-type channels.…”