Joint publication of the Carrell and Hopfner lab "Novel Poxin Stable cGAMP-Derivatives Are Remarkable STING Agonists"

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 responsecharacterized by the production of type I interferonsand  cytokines.  The  development  of  STING-binding  molecules  with both  agonistic  as  well  as  antagonistic  properties  is  currently  of tremendous  interest  to induce  or  enhance  antitumoror  antiviral immunityon  the  one  hand,  or  to treat  autoimmune  diseaseson the other  hand. To  escape the  host  innate immune  recognition,  some viruses encodepoxin endonucleases that cleave 2’,3’-cGAMP. Here we  report  that dideoxy-2’,3’-cGAMP(1)  andanalogsthereof,which lack  the  secondary ribose-OH  groups,form  a  group  ofpoxin-stable STINGagonists. Despite theirreduced affinity to STING, particularlythe  compound  constructed  from  two  A  nucleosides,dideoxy-2’,3’-cAAMP(2),features an unusually high antitumorresponsein mice. To read the full paper click here.

Stazzoni S, Böhmer DFR, Hernichel F, Özdemir D, Pappa A, Drexler D, Bauernfried S, Witte G, Wagner M, Veth S, Hopfner K-P, Hornung V, König LM and Carell T (2022) Novel Poxin Stable cGAMP‐Derivatives Are Remarkable STING AgonistsAngew Chemie Int Ed, doi: 10.1002/anie.202207175 Link