Multidisciplinary Advances Address the Challenges in Developing Drugs against Transient Receptor Potential Channels to Treat Metabolic Disorders

Transient receptor potential (TRP) channels are cation channels that regulate key physiological and pathological processes in response to a broad range of stimuli. Moreover, they systemically regulate the release of hormones, metabolic homeostasis, and complications of diabetes, which positions them as promising therapeutic targets to combat metabolic disorders. Nevertheless, there are significant challenges in the design of TRP ligands with high potency and durability. Herein we summarize the four challenges as hydrophobicity, selectivity, mono-target therapy, and interspecies discrepancy. We present 1134 TRP ligands with diversified modes of TRP-ligand interaction and provide a detailed discussion of the latest strategies, especially cryogenic electron microscopy (cryo-EM) and computational methods. We propose solutions to address the challenges with a critical analysis of advances in membrane partitioning, polypharmacology, biased agonism, and biochemical screening of transcriptional modulators. They are fueled by the breakthrough from cryo-EM, chemoinformatics and bioinformatics. The discussion is aimed to shed new light on designing next-generation drugs to treat obesity, diabetes and its complications, with optimal hydrophobicity, higher mode selectivity, multi-targeting and consistent activities between human and rodents.