STING (stimulator of interferon genes) is a dimeric protein localized in the membrane of endoplasmatic reticulum (ER) where it acts as a receptor of cyclic dinucleotides (CDNs) second messengers involved in the innate immune system. After triggering by CDNs of bacterial or host origin, it is capable to activate both NFκB and IRF3 transcription pathways to induce type I interferons (INF‑α and INF‑β), which leads to potent antibacterial and antiviral state of organism. Therefore, STING is being investigated as a potential pharmacophore for the treatment of viral diseases. A natural endogenous agonist of STING is 2 ́3 ́cycloGMPAMP (2 ́3 ́cGAMP). This CDN is produced by cytosolic DNA sensor cyclicGMPAMP synthase (cGAS). On the basis of 2 ́3 ́-cGAMP and also CDNs of bacterial origin (c-di-AMP, c-d-GMP or c-di-IMP), novel STING agonists were designed. Among the very interesting ones are fluorinated analogues of CDNs, which exhibit higher potency in induction of type I interferons than their nonfluorinated parent compounds such as fluorinated 3‘3‘cGAMP. We have successfully co-crystallized human wild type STING with fluorinated and non-fluorinated 3‘3‘cGAMP and 3‘3‘cdiAMP. Surprisingly, our structural analysis revealed just slight differences between these structures. Subsequent computational analysis suggested that the hydrophobic effect together with conformational strain energy are responsible for the increased activity.