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

Area of Science:

• Immunology
• Molecular Biology
• Drug Discovery

Background:

• Hyperactive stimulator of interferon genes (STING) signaling drives inflammatory diseases.
• Targeting STING offers a therapeutic strategy for managing inflammation.

Purpose of the Study:

• To identify and characterize novel inhibitors of human STING (hSTING).
• To evaluate the therapeutic potential of a macrocyclic peptide inhibitor in preclinical models of inflammation.

Main Methods:

• Discovery of a macrocyclic peptide (P1) using a pseudonatural macrocyclic peptide platform.
• In vitro cellular assays to assess P1's effect on hSTING translocation and downstream signaling.
• Crystallographic analysis of P1-bound hSTING to elucidate the binding mechanism.
• In vivo studies using nanoparticle-formulated P1 (Nano-P1) in humanized STING mice models.

Main Results:

• P1 binds to the cyclic nucleotide binding domain of hSTING, trapping it in an inactive conformation.
• P1 inhibits STING-ER translocation, reducing interferon-β and pro-inflammatory cytokine production.
• Nano-P1 effectively dampened inflammation in cellular and in vivo models, including Trex1-deficient mice.
• Nano-P1 treatment improved growth and survival in mice with STING-driven inflammation, with no observed toxicity.

Conclusions:

• The macrocyclic peptide P1 is a potent inhibitor of hSTING.
• Nano-P1 demonstrates significant therapeutic potential for treating inflammatory conditions driven by hyperactive STING.
• The safety profile of Nano-P1 supports its potential for clinical applications.