Good news! Cancer is history (soon)! What a complexity!
".... H-151, a cysteine-reactive compound that targets C88 and C91 ..." Notice how the authors switched from H-151 to C91 between news release and research article.
"... Historically, research on STING has overwhelmingly focused on activating the pathway to recruit immune cells that attack tumors. However, inhibiting the pathway is understudied and mounting evidence suggests that overactivation of STING may turn the immune system against healthy cells. This dual nature of activation and inhibition of STING make the pathway a powerful but complex target for drug development ...
"Our study evaluated the effectiveness of H-151, the most advanced inhibitor of human STING, which has shown promise in reversing cognitive decline in mice but has failed to block human STING signaling in purified human blood cells," ... "Our results show that in humans, the target site of H-151 lacks a pocket that is found in mouse STING, and without it, drug tailoring is incredibly challenging."
H-151 is a powerful STING inhibitor because once it binds to its target, it does not let go. It also targets a section of the STING pathway that is necessary for mouse STING signaling, but not humans. This fundamental mechanistic difference explains the discrepancies in inhibitor effectiveness between the two species, highlighting the limitations of using mouse models to predict human outcomes in STING-targeted therapy development. ..."
From the abstract:
"The stimulator of interferon genes (STING) innate immune pathway can exacerbate inflammatory diseases when aberrantly activated, emphasizing an unmet need for STING antagonists. However, no inhibitors have advanced to the clinic because it remains unclear which mechanistic step(s) of human STING activation are crucial for inhibition of downstream signaling.
Here we report that C91 palmitoylation is not universally necessary for human STING signaling.
Instead, evolutionarily-conserved C64 is basally palmitoylated and is crucial for preventing unproductive STING oligomerization. The effects of palmitoylation at C64 and C91 converge on the control of intradimer disulfide bond formation at C148.
Together, dynamic equilibria of these cysteine post-translational modifications allow proper STING ligand-binding domain self-assembly and scaffolding function. Given this complex landscape, we took inspiration from STING’s natural autoinhibitory mechanism and identified an eight-amino-acid peptide that binds a defined pocket at the oligomerization interface, setting the stage for future therapeutic development."
Researchers reveal key differences in STING inhibition between humans and mice (original news release) "Arc Institute and Stanford University scientists highlight problems with ongoing STING inhibitor development strategies and offer an alternative explanation for how STING works in human autoimmunity and inflammation."
Human STING oligomer function is governed by palmitoylation of an evolutionarily conserved cysteine (this appears to be the earlier preprint version of this paper, open access)
Graphical abstract
No comments:
Post a Comment