Human STING-specific macrocyclic peptide Nano-P1 displays limited toxicity to MEFs and potently suppresses cGAS-STING activation

We identified a macrocyclic peptide, named P1, which binds to human STING (hSTING) by a new platform for the discovery of pseudo-natural macrocyclic peptides. Nano-P1, the nanoparticle form to increase P1 cellular membrane permeability, inhibited the 2'3'-cGAMP induced hSTING activation in Mouse Embryonic Fibroblasts (MEFs).

In cellular experiments, Nano-P1 effectively blocked the translocation of hSTING from endoplasmic reticulum (ER) to the trans-Golgi network, increasing the accumulation of hSTING on ER, and thus interrupted the downstream STING signaling transduction, which resulted in reduced production of IFN-β and pro-inflammatory cytokines, the major effectors of STING pathway. Furthermore, in vitro data showed a limited toxicity of Nano-P1 toward MEFs, preliminarily supporting its safety profile in most cell types.