A human-STING specific macrocyclic peptide suppresses cGAS-STING-induced inflammation

Suppression of hyperactive stimulator of interferon genes (STING) may provide therapeutic benefits to treat inflammatory diseases. We identified a macrocyclic peptide, named P1, which binds to human STING (hSTING) by a new platform for the discovery of pseudonatural macrocyclic peptides. In cellular experiments, 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 signalling transduction, which resulted in reduced production of interferon-β (IFN-β) and proinflammatory cytokines, the major effectors of the STING pathway. Mechanistically, the crystallographic structure of P1-bound hSTING reveals that P1 binds to the cyclic nucleotides binding domain of hSTING dimers, the same domain as 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) (2'3'-cGAMP) binds, and that P1-bound hSTING dimers are trapped in an 'open' conformation due to 38°-rotated wings compared with the 'closed' conformation associated with 2'3'-cGAMP-mediated hSTING activation. Nano-P1, the nanoparticle form to increase its cellular membrane permeability, dampened the infectious inflammation induced by herpes simplex virus type 1 both in human cells and in humanised-STING (hSTING^+/+) mice. Trex1-deficient hSTING^+/+ mice, which develop uncontrolled type I interferon-driven inflammation with growth failure and early lethality, were used to assess the effects of STING inhibition. Treatment with Nano-P1 suppressed the systemic inflammation, restored the regular growth, and substantially extended the survival of the otherwise runt and short-lived mice. Furthermore, neither in vitro nor in vivo experiments showed toxicity of Nano-P1, proving its safety for potential clinical application. Therefore, the macrocyclic peptide-based Nano-P1, an hSTING inhibitor, has great potential for treating the inflammation resulting from hyperactive STING.