Identifikace a detailní charakterizace sloučenin inhibujících endonukleasovou aktivitu RNA polymerasy viru chřipky a viru RVFV

Kráľ, Michal

Influenza and bunyaviruses pose significant public health challenges due to their high mutation rates, zoonotic potential, and limited antiviral therapies. Due to these attributes, both viruses are selected by the World Health Organization as the priority pathogens. This dissertation focuses on the design, synthesis, and structural characterization of small-molecule inhibitors targeting the viral polymerases of these viruses. The first part of this work explores flavonoid- and benzotropolone-derived scaffolds as inhibitors of the influenza PA endonuclease, a key component of the viral RNA-dependent RNA polymerase. Through scaffold-hopping and bioisosteric design, metabolically stable pseudoflavonoids and purpurogallin-4-carboxamides were developed, exhibiting submicromolar inhibition of the endonuclease and strong antiviral activity in human lung cell-derived tissue cultures. Structural analyses confirmed metal ion coordination within the catalytic site and validated the intended binding mode. Further optimization at the C-8 position of luteolin yielded arylated derivatives with nanomolar potency and high metabolic stability, representing one of the most active flavone-derived inhibitor series to date. All biochemical and cellular assays employed in this work is supported by structural data arising...

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