Arabinose- and xylose-modified analogs of 2′,3′-cGAMP act as STING agonists Journal Article

   


Authors: Xie, W.; Lama, L.; Yang, X.; Kuryavyi, V.; Bhattacharya, S.; Nudelman, I.; Yang, G.; Ouerfelli, O.; Glickman, J. F.; Jones, R. A.; Tuschl, T.; Patel, D. J.
Article Title: Arabinose- and xylose-modified analogs of 2′,3′-cGAMP act as STING agonists
Abstract: Stimulator of interferon genes (STING) agonists are promising candidates for vaccine adjuvants and antitumor immune stimulants. The most potent natural agonist of STING, 2′,3′-cyclic GMP-AMP (2′,3′-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′,3′-cGAMP containing 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′,3′-cGAMP mimetics that induce the “closed” 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′,3′-cGAMP at inducing IFN-β secretion from human THP1 cells. The arabinose- and xylose-modified 2′,3′-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. © 2023 Elsevier Ltd
Keywords: mouse; animal; metabolism; animals; mice; vaccine adjuvants; cancer therapeutics; nucleotides, cyclic; humans; human; arabinose; cyclic guanosine monophosphate-adenosine monophosphate; cyclic nucleotide; xylose; 2′,3′-cgamp; analogs targeting sting; arabinose and xylose analogs; resistance to enpp1; stability in human serum; adjuvants, vaccine; vaccine adjuvant
Journal Title: Cell Chemical Biology
Volume: 30
Issue: 11
ISSN: 2451-9456
Publisher: Cell Press  
Date Published: 2023-11-16
Start Page: 1366
End Page: 1376.e7
Language: English
DOI: 10.1016/j.chembiol.2023.07.002
PUBMED: 37536341
PROVIDER: scopus
PMCID: PMC10808274
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85170033652&doi=10.1016%2fj.chembiol.2023.07.002&partnerID=40&md5=2994355251240580af2a9c2f4ff6c27b
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Dinshaw Patel -- Source: Scopus
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MSK Authors
  1. Ouathek Ouerfelli
    100 Ouerfelli
  2. Dinshaw J Patel
    477 Patel
  3. Vitaly V Kuryavyi
    27 Kuryavyi
  4. Guangli Yang
    34 Yang
  5. Wei Xie
    19 Xie
  6. Xuejing Yang
    11 Yang
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