Development\nof an Intravenously Stable Disulfide-Rich\nPeptide for the Treatment of Chemotherapy-Induced Neuropathic Pain

α-conotoxins (α-Ctxs), a class of disulfide-rich\nconopetides,\nare excellent drug leads due to their small size, high selectivity,\nand potency for specific membrane receptors and ion channels involved\nin pain transmission. However, their high susceptibility to proteolytic\ndegradation limits their therapeutic potential. In this study, we\ndesigned and synthesized a series of conformationally stable analogues\nof α-Ctx Mr1.1[S4Dap] using various structural optimization\nstrategies. The Mr1.1[S4Dap, C16Pen] analogue maintained potency at\nhuman α9α10 nicotinic acetylcholine receptors, with a\nhalf-maximal inhibitory concentration (IC<sub>50</sub>) of 4 nM. It\nexhibited over a 5-fold increase in serum stability compared to Mr1.1[S4Dap],\nwithout disrupting its overall conformation. Furthermore, intravenous\napplication of Mr1.1[S4Dap, C16Pen] showed potent analgesic activity\nin oxaliplatin-induced cold allodynia, indicating a high potential\nfor drug development. Overall, the results from this study provide\nvaluable insights for optimizing the serum stability of disulfide-rich\npeptides in future therapeutic applications.