Pain is a quite frequent complaint after injuries and accompanying different pathologies, which remains poorly treated for a number of patients. Pain involves extremely complex/interrelated series of signaling and modulatory pathways of the nervous system. Within them, the contribution to pain sensation and transmission of different ion channels and regulatory proteins center the attention in recent years. Here, peptides are paying a key role in better understanding how the direct modulation of these channels or the inhibition of the interaction with regulatory protein partners can affect nociceptive behaviors. A key success in this field was the commercialization in 2004 of the naturally occurring ω-conotoxin MVIIA (Ziconotide, Prialt®), for the intrathecal therapy of severe chronic pain in patients refractory to morphine treatment. Since this compound, which blocks directly a subtype of voltage-gated Ca2+ channels, is associated with a number CNS-related adverse events, recent research approaches to safer analgesics are devoted to modulate protein-protein interactions within the pain receptome, especially those involving ion channels. In this sense, representative examples of new peptides with important analgesic activities are TAT-CBD3 and analogues, targeting the CaV2.2-CRMP2 interaction, TAT-TRPV1726-745 or TAT-AKAP326-336, acting as antagonists of the TRPV1-AKAP79 interaction, and T100-mut interfering within the ternary complex TRPA1-TRPV1-Tmem100. These examples are new tools to better understand pain pathways and could be the starting point for medicinal chemistry programs towards innovative analgesics. As the knowledge on intercommunication between receptors, channels and pain regulatory proteins (pain receptome) increases, the opportunities for peptides in this field multiply.
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Contributed by Rosario González-Muñiz
Rosario is a Senior Researcher at the Medicinal Chemistry Institute (IQM-CSIC), Madrid. She is involved in peptides, secondary structure mimics and small-molecule peptidomimetics of application in biological/medicinal chemistry programs, especially related to the modulation of ion channels and associated proteins.