IOCB Prague

Gabriel Birkuš Group

HBV Cure
Targeted Research Group
BIO cluster

About our group

We are a cross-functional team consisting of medicinal chemists, virologists, immunologists, computational chemists, and biochemists focused on discovery of novel therapies to treat chronic hepatitis B, cancer, and inflammatory disorders. In collaboration with our international partners, we are currently involved in the identification of novel agonists and antagonists of the cGAS-STING pathway, which plays a crucial role in the recognition of dsDNA in the cytosol. Activation of the pathway by viral, microbial, or tumor-derived dsDNA results in expression of type I IFNs and other inflammatory cytokines. This ultimately leads to induction of innate and adaptive immune responses enabling clearance of the infection or inhibition of tumor growth. Simultaneously, an abnormal overactivation of the pathway has been implicated in autoimmune disorders such as systemic lupus erythematosus and Aicardi-Goutières syndrome. We have prepared several classes of novel cyclic dinucleotides (CDNs) with potent agonistic activity toward all STING haplotypes. Besides employing conventional chemical synthesis, we have also utilized enzymatic preparation of CDNs. For that purpose, we identified several promiscuous bacterial and vertebrate cyclic dinucleotide synthases, which have allowed for an efficient, one-step preparation of CDNs from NTP analogues. Moreover, we have developed methods for the synthesis of lipophilic prodrugs of CDNs with improved cellular activity compared to their parents. Currently, we are applying our expertise in drug discovery to identify inhibitors of the enzyme cGAS and antagonists of the STING adaptor protein.

[hepatitis B virus microphotography in header © Alain Grillet, Sanofi Pasteur]