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National Repository of Grey Literature 2 records found  Search took 0.01 seconds. 
Effect of selected compounds on NMPylation of nsp9 SARS-CoV-2 catalyzed by NiRAN domain of nsp12 SARS-CoV-2
 Fedák, Michal ; Šilhán, Jan (advisor) ; Vaněk, Ondřej (referee)
SARS-CoV-2 pandemic that begun in the end of 2019 caused over 770 milion confirmed cases of infection and almost 7 milion deaths worliwide. Despite pandemic being suppressed thanks to vaccines and restriction measures, the research of new medication targeting this virus continues. One of the possible targets of SARS-CoV-2 is nonstructural protein 9 (nsp9), which is essential for virus repliation. Just recently it was revealed that this protein can covalently bind nukleoside monophosphate (NMPylation) or RNA chain of various length (RNAylation). These reactions are catalyzed by nidovirus RNA-dependent RNA polymerase (RdRp) asociated nucleotidyltransferase (NiRAN) domain of nonstuctural protein 12 (nsp12). RNAylation of nsp9 showed to be crucial step in synthesis of RNA cap. The function of NMPylation was not jet revealed, but it is believed that this modification of nsp9 could play a role in priming of RNA synthesis. Some studies have already investigated inhibition of NMPylation. In this diploma thesis recombinant nsp9 was prepared and used in NMPylation reactions. Negative effect of DMSO on nsp9 NMPylation was observed. Three compounds (saquinavir, darunavir and conivaptan) selected based on the results of in silico studies did not show ability to inhibit NMPylation of nsp9. Next, it was confirmed...
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Effect of pH on vandetanib oxidation
 Fedák, Michal ; Indra, Radek (advisor) ; Otáhalová, Barbora (referee)
Vandetanib is anticancer drug used mainly for targeted therapy of medullary thyroid carcinoma. It acts as inhibitor of tyrosine kinase and shows selectivity for vascular endothelial growth factor 2 (VEGFR-2) and epidermal growth factor (EGFR). It also inhibits rearranged during transfection (RET) tyrosine kinase activity. Vandetanib is metabolized by cytochromes P450 (CYPs) and flavin-containing monooxygenases (FMOs) in organism of humans as well as experimental animals. CYPs oxidize vandetanib to N-desmethylvandetanib. FMOs are responsible for the formation of vandetanib N-oxide. This bachelor thesis studies effect of pH on vandetanib oxidation by CYPs a FMOs present in rat hepatic microsomes induced by different agents. Collected data show that in majority of series, optimal pH levels for oxidation of vandetanib by CYPs and FMOs are similar to a large extend. The highest amount of N- desmethylvandetanib was observed mostly at the pH 8,5. Vandetanib N-oxide was also produced in the highest quantity at the same level of pH in majority of series. Results suggest that N-desmethylvandetanib is formed at levels of pH which do not fit in interval of pH for optimal CYP activity. This finding is apparently due to a fact that presence of vandeanib in its neutral form, which is effectively oxidized by CYP,...
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