Research Progress in Area 4 方向 ( 四 ) 課題進展 193 Abstract TRPV1 channel is involved in modulating pain sensation and therefore is an important target for treating chronic pain, which affects >10% of the populations worldwide. Currently, there is no effective and safe drugs targeting TRPV1. In collaboration with Prof. Peiyuan Qian’s laboratory, we screened approximately 210 marine bacterial extracts and discovered 17 lead compounds in high-throughput screening assays. The effect of the 17 compounds on TRPV1 were further verified at the single-channel level in patch-clamp studies. Furthermore, two compounds F11 and F28 were tested in the capsaicin-induced pain sensation assay in the mouse and showed robust inhibitory effects. In summary, our study identified several novel inhibitors and activators of TRPV1 channel from marine natural products. Research Activities and Progress • Screened total 210 compounds (all repeated at least in triplicates; 32 compounds repeated 6-9 times); • Identified 17 lead compounds: 14 inhibitors and 3 activators; • The 17 lead compounds were subjected to highresolution patch-clamp studies; • F11, F28, and compound 258 among the 14 inhibitors showed the strongest inhibitory effect on TRPV1 channel in patch-clamp studies; • All the activators showed moderate/good effects relative to classical TRPV1 activator capsaicin in patch-clamp studies; • F11 and F28 were tested in in-vivo pain assays. F 11 and F28 are as effective as capsazepine, a commercially available inhibitor of capsaicin, in blocking capsaicin-induced pain sensation. Key Findings • High-throughput fluorescent FM4-64 uptake assays and high-resolution patch-clamp assay of TRPV1 channel activity were fast and reliable methods; • Total 210 compounds were tested and 17 of them were found to have inhibitory or excitatory effects on TRPV1 channel in FM4-64 uptake assays; • F11, F28, and compound 258 among the 14 inhibitors showed the strongest inhibitory effect on TRPV1 channel in patch-clamp studies; • F 11 and F28 are shown to be as effective as capsazepine in blocking capsaicin-induced pain sensation in the mouse. Research Output Publication 4 Trained personnel 3 Discovery of Ion-channel Drugs from Marine Natural Products Prof. Pingbo Huang The Hong Kong University of Science and Technology Fig 1. High throughput FM4-64 dye uptake-based drug screening.
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