TRIV1 is a non-selective cation channel critical to pain sensation and hence being targeted for chronic pain treatment. However, there are no FDA-approved TRPV1 antagonist for clinical uses due to their potential severe side effects. Therefore, extensive research has been conducted to identify new TRPV1 modulators that are safe and effective for clinical use. Marine bacterial metabolites are known to have high bioactivities, which can be preferred source of potential channel modulators. In this project, we have utilized a screening method based on high-throughput FM4-64 dye-uptake assay to identify TRPV1 modulators. We found that chrexanthomycins outperformed other candidates from marine bacterial metabolites library in TRPV1 inhibition. Hence, we were particularly interested in the pe...[ Read more ]

TRIV1 is a non-selective cation channel critical to pain sensation and hence being targeted for chronic pain treatment. However, there are no FDA-approved TRPV1 antagonist for clinical uses due to their potential severe side effects. Therefore, extensive research has been conducted to identify new TRPV1 modulators that are safe and effective for clinical use. Marine bacterial metabolites are known to have high bioactivities, which can be preferred source of potential channel modulators. In this project, we have utilized a screening method based on high-throughput FM4-64 dye-uptake assay to identify TRPV1 modulators. We found that chrexanthomycins outperformed other candidates from marine bacterial metabolites library in TRPV1 inhibition. Hence, we were particularly interested in the performance of chrexanthomycins, and we found that cC and cF outperformed other chrexanthomycins in TRPV1 inhibition, demonstrated IC₅₀ values of 0.9 μM and 2.1 μM, respectively. We subsequently validated the TRPV1 inhibitory effects of cC and cF through high-resolution patch-clamp electrophysiological assays. Our study also demonstrated that cC and cF posed TRPV1 inhibitory effects in an in vivo mouse model without causing any observable health issues. Furthermore, chrexanthomycins have a distinct structure different from existing TRPV1 antagonist, capsazepine, which suggests novel TRPV1 binding sites during inhibition. Collectively, our project identified a new group of compounds, chrexanthomycins, as TRPV1 inhibitors, and their distinctive pharmacophores provided new insights into the mechanisms of TRPV1 inhibition. Further evaluation of the potency and safety of chrexanthomycins can assist in the development of cC and cF as potential commercial drugs. In addition, investigating the interaction between chrexanthomycins and TRPV1 channel may lead to the design and development of a novel group of TRPV1 antagonists for clinical use without posing any severe side effects.