Rational Design of a Modality‐Specific Inhibitor of TRPM8 Channel against Oxaliplatin‐Induced Cold Allodynia

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.

A common mechanism of temperature-sensing in thermoTRP channels

“…However, many blockers of these channels developed for analgesia caused changes in body temperature and blunt of acute temperature sensation in patients, leading to failures in clinical trials (Gavva, 2009; Kort and Kym, 2012). Understanding the temperature sensing mechanisms and temperature-induced conformational changes will help develop modality-specific blockers, like the cyclic peptide DeC-1.2 we recently designed to inhibit the ligand gating of TRPM8 without affecting cold activation (Aierken et al, 2021), to minimize adverse side effects while exerting analgesic effects.…”

Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design

“…However, numerous experimental ion channel structures have been determined with the cryo-EM technique nowadays, including the human hERG structures that were resolved in 2017 ( Wang and MacKinnon, 2017 ), which might provide a significant cornerstone of the structure-based prediction. Beneficial from the high-resolution structures of the TRPM8 channel in various states ( Yin et al, 2018 ; Diver et al, 2019 ; Yin et al, 2019 ), Yang et al conducted a rational design of the TRPM8 channel and developed a modality-specific inhibitor DeC-1.2, which showed the potential as a novel analgesic against oxaliplatin-induced neuropathic pain ( Aierken et al, 2021 ). Additionally, various protein-folding and modeling tools were also developed ( Baek et al, 2021 ; Jumper et al, 2021 ), which provide an alternative way for protein structure modeling besides the classic homology modeling approach ( Huang et al, 2022 ), and may also contribute as a start point for the construction of single-particle cryo-EM structures ( Figure 3 ).…”

In Vitro and In Vivo Pharmacological Characterization of a Novel TRPM8 Inhibitor Chemotype Identified by Small-Scale Preclinical Screening

“…TRPM8 antagonism is deeply related to analgesic in vivo effects and has been proposed as a suitable pharmacological strategy for the treatment of chronic pain, migraine, and painful syndromes [39][40][41]. TRPM8 antagonists are particularly known to counteract the chemotherapy-induced neuropathic pain evoked by oxaliplatin [24,[27][28][29]. For these reasons we challenged compound 14 (BB 0322703) in vivo using the oxaliplatin-induced cold hypersensitivity assay.…”

“…Of note, the antifungal drug clotrimazole has strong TRPM8 antagonistic activity [22], while SKF96365, a non-specific blocker of several types of calcium channels, also inhibits TRPM8 in vitro [23]. Finally, a cyclic peptide specifically targeting the outer pore of the channels has been described as a potent antagonist endowed with anti-allodynic effects [24]. Nevertheless, none of the described TRPM8 antagonists has reached the clinical stage, so far [25].…”