Abstract:

<p>Stimulator of interferon genes (STING) agonists are promising candidates for vaccine adjuvants and antitumor immune stimulants. The most potent natural agonist of STING, 2&#39;,3&#39;-cyclic GMP-AMP (2&#39;,3&#39;-cGAMP), is subject to nuclease-mediated inherent metabolic instability, thereby placing limits on its clinical efficacy. Here, we report on a new class of chemically synthesized sugar-modified analogs of 2&#39;,3&#39;-cGAMP containing&nbsp;arabinose and xylose sugar derivatives that bind mouse and human STING alleles with high affinity. The co-crystal structures demonstrate that such analogs act as 2&#39;,3&#39;-cGAMP mimetics that induce the &quot;closed&quot; conformation of human STING. These analogs show significant resistance to hydrolysis mediated by ENPP1 and increased stability in human serum, while retaining similar potency as 2&#39;,3&#39;-cGAMP at inducing IFN-β secretion from human THP1 cells. The arabinose- and xylose-modified 2&#39;,3&#39;-cGAMP analogs open a new strategy for overcoming the inherent nuclease-mediated vulnerability of natural ribose cyclic nucleotides, with the additional benefit of high translational potential as cancer therapeutics and vaccine adjuvants.</p>