Petra Břehová, PhD
+420 220 183 207
Selected papers
Synthesis and Biological Evaluation of Phosphoester and Phosphorothioate Prodrugs of STING Agonist 3′,3′-c-Di(2′F,2′dAMP)
Journal of Medicinal Chemistry 64 (11): 7596–7616 (2021)
Cyclic dinucleotides (CDNs) are second messengers that bind to the stimulator of interferon genes (STING) and trigger the expression of type I interferons and proinflammatory cytokines. Here we evaluate the activity of 3′,3′-c-di(2′F,2′dAMP) and its phosphorothioate analogues against five STING allelic forms in reporter-cell-based assays and rationalize our findings with X-ray crystallography and quantum mechanics/molecular mechanics calculations. We show that the presence of fluorine in the 2′ position of 3′,3′-c-di(2′F,2′dAMP) improves its activity not only against the wild type (WT) but also against REF and Q STING. Additionally, we describe the synthesis of the acyloxymethyl and isopropyloxycarbonyl phosphoester prodrugs of CDNs. Masking the negative charges of the CDNs results in an up to a 1000-fold improvement of the activities of the prodrugs relative to those of their parent CDNs. Finally, the uptake and intracellular cleavage of pivaloyloxymethyl prodrugs to the parent CDN…
Acyclic nucleoside phosphonates with 2-aminothiazole base as inhibitors of bacterial and mammalian adenylate cyclases
European Journal of Medicinal Chemistry 222: 113581 (2021)
Latest publications
Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-b]pyridazine Derivatives Identified by Scaffold Hopping
Journal of Medicinal Chemistry 2023: Early View
Identifying a selective inhibitor of autophagy that targets ATG12-ATG3 protein-protein interaction
Autophagy 19 (8): 2372-2385 (2023)
Synthetic Stimulator of Interferon Genes (STING) Agonists Induce a Cytokine-Mediated Anti-Hepatitis B Virus Response in Nonparenchymal Liver Cells
ACS Infectious Diseases 9 (1): 23–32 (2023)
Discovery of isonucleotidic CDNs as potent STING agonists with immunomodulatory potential
Structure 30 (8): 1146–1156 (2022)