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Protein STING targeting for chronic hepatitis B treatment
Pimková Polidarová, Markéta ; Birkuš, Gabriel (advisor) ; Forstová, Jitka (referee) ; Rumlová, Michaela (referee)
Chronic hepatitis B (CHB) is an infectious disease caused by the hepatotropic hepatitis B virus (HBV). CHB affects millions of people worldwide, but the treatment options are still limited, and virus elimination is rarely achieved. The immunomodulatory approaches towards CHB treatment are recently being investigated. In this thesis, we focused on the anti-HBV potential of the cyclic- GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) DNA-sensing innate immunity pathway, which upon activation leads to the secretion of proinflammatory cytokines. We screened synthetic cyclic dinucleotide (CDN)-based STING agonists and their lipophilic prodrugs prepared in our laboratory in reporter cell lines and peripheral blood mononuclear cells (PBMC). We selected candidate compounds with superior cGAS-STING pathway activation properties compared to the natural eukaryotic STING agonist. We identified 3′,3′-c-di(2′-fluoro,2′- deoxyAMP) to have improved cGAS-STING pathway activation properties over the five most abundant STING isoforms found in the humans, including the variants that do not respond well to 3′,3′-CDNs. The symmetric bis-pivaloyloxymethyl prodrug of 3′,3′-c-di(2′-fluoro,2′-deoxyAMP) further increased the activity of parent CDNs by enhancing their intracellular entry. We showed that the...
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