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Abstract Platinum‐based compounds in chemotherapy such as oxaliplatin often induce peripheral neuropathy and neuropathic pain such as cold allodynia in patients. Transient Receptor Potential Melastatin 8 (TRPM8) ion channel is a nociceptor critically involved in such pathological processes. Direct blockade of TRPM8 exhibits significant analgesic effects but also incurs severe side effects such as hypothermia. To selectively target TRPM8 channels against cold allodynia, a cyclic peptide DeC‐1.2 is de novo designed with the optimized hot‐spot centric approach. DeC‐1.2 modality specifically inhibited the ligand activation of TRPM8 but not the cold activation as measured in single‐channel patch clamp recordings. It is further demonstrated that DeC‐1.2 abolishes cold allodynia in oxaliplatin treated mice without altering body temperature, indicating DeC‐1.2 has the potential for further development as a novel analgesic against oxaliplatin‐induced neuropathic pain.

Abstract Transient receptor potential vanilloid 1 (TRPV1) ion channel is a nociceptor critically involved in pain sensation. Direct blockade of TRPV1 exhibits significant analgesic effects but also incurs severe side effects such as hyperthermia, causing failures of TRPV1 inhibitors in clinical trials. In order to selectively target TRPV1 channels that are actively involved in pain‐sensing, peptidic positive allosteric modulators (PAMs) based on the high‐resolution structure of the TRPV1 intracellular ankyrin‐repeat like domain are de novo designed. The hotspot centric approach is optimized for protein design; its usage in Rosetta increases the success rate in protein binder design. It is demonstrated experimentally, with a combination of fluorescence resonance energy transfer (FRET) imaging, surface plasmon resonance, and patch‐clamp recording, that the designed PAMs bind to TRPV1 with nanomolar affinity and allosterically enhance its response to ligand activation as it is designed. It is further demonstrated that the designed PAM exhibits long‐lasting in vivo analgesic effects in rats without changing their body temperature, suggesting that they have potentials for developing into novel analgesics.