Overview
- Researchers report that the small molecule SBI-553 binds the inside of the neurotensin receptor 1 and biases downstream responses.
- The study identifies a dual mechanism in which SBI-553 acts as a molecular bumper for some G proteins and as molecular glue for others.
- Testing 29 close analogs revealed that small chemical changes produced large, predictable shifts across G protein subtypes and beta-arrestins.
- In mice, a related compound (SBI-593) that did not fully block Gq failed to prevent hypothermia, supporting a link between specific G protein activity and side effects.
- The team says the intracellular site is druggable, a prospect that could expand targets beyond the extracellular focus of most GPCR drugs, pending further validation.