Conopeptides as Modulators of Pain and Inflammation in Chemotherapy-Induced Peripheral Neuropathy by Targeting α7 and α9 Nicotinic Acetylcholine Receptors.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and debilitating complication of cancer treatment, characterized by sensory dysfunction, including allodynia and hyperalgesia. Despite its clinical significance, there are no FDA-approved preventive options for CIPN, and current symptom management remains limited in effectiveness. Recent insights into CIPN's underlying mechanisms have highlighted the roles of neuroimmune interactions and ion channel dysfunction, particularly involving nicotinic acetylcholine receptors (nAChRs). Notably, the α7 and α9 nAChR subtypes play a critical role in controlling neuronal excitability and inflammatory responses in both peripheral and central sensory pathways. Conopeptides, a group of disulfide-rich peptides from cone snail venom, have attracted attention as highly selective modulators of ion channels involved in pain pathways. This review highlights α-conotoxins targeting nAChRs, specifically RgIA4 and GeXIVA[1,2], which have dual therapeutic effects by blocking pain signals and reducing neuroinflammation. We explore the structural variety and functional specificity of conopeptides, their mechanisms in CIPN animal models, and their potential as disease-modifying agents. The review also covers recent advances in peptide engineering aimed at improving cross-species compatibility, receptor selectivity, and serum stability of conopeptides in targeting nAChR. The article highlights the potential of nAChR-targeting conopeptides as next-generation treatments for CIPN, outlining key challenges and future directions for clinical development.