Novel Poxin Stable cGAMP-Derivatives Are Remarkable STING Agonists

  • Angew Chem Int Ed Engl. 2022 Oct 4;61(40):e202207175. doi: 10.1002/anie.202207175.
Samuele Stazzoni  1  2 ,  Daniel F R Böhmer  3 ,  Fabian Hernichel  2 ,  Dilara Özdemir  2 ,  Aikaterini Pappa  2 ,  David Drexler  4 ,  Stefan Bauernfried  4 ,  Gregor Witte  4 ,  Mirko Wagner  2 ,  Simon Veth  2 ,  Karl-Peter Hopfner  4 ,  Veit Hornung  4 ,  Lars M König  3 ,  Thomas Carell  2
Affiliations
  • 1. New address: Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, 53100, Siena, Italy.
  • 2. Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.
  • 3. Division of Clinical Pharmacology, University Hospital, Ludwig-Maximilians-Universität München, Lindwurmstr. 2a, 80337, Munich, Germany.
  • 4. Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 25, 81377, Munich, Germany.
PMID: 35876840 DOI: 10.1002/anie.202207175
Abstract

2',3'-cGAMP is a cyclic A- and G-containing dinucleotide second messenger, which is formed upon cellular recognition of foreign cytosolic DNA as part of the innate immune response. The molecule binds to the adaptor protein STING, which induces an immune response characterized by the production of type I interferons and cytokines. The development of STING-binding molecules with both agonistic as well as antagonistic properties is currently of tremendous interest to induce or enhance antitumor or Antiviral immunity on the one hand, or to treat autoimmune diseases on the Other hand. To escape the host innate immune recognition, some viruses encode poxin endonucleases that cleave 2',3'-cGAMP. Here we report that dideoxy-2',3'-cGAMP (1) and analogs thereof, which lack the secondary ribose-OH groups, form a group of poxin-stable STING agonists. Despite their reduced affinity to STING, particularly the compound constructed from two A nucleosides, dideoxy-2',3'-cAAMP (2), features an unusually high antitumor response in mice.

Keywords
Antiviral Compound; Immuno Oncology; Poxins; STING; cGAMP.
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