prikaz prve stranice dokumenta Bakterijske i virusne makrodomene – struktura, funkcija i terapeutski potencijal
Embargo period 2024-11-23
doctoral thesis
Bakterijske i virusne makrodomene – struktura, funkcija i terapeutski potencijal
Zagreb: University of Zagreb, Faculty of Science, 2023. urn:nbn:hr:217:629915
Hloušek-Kasun, Andrea
University of Zagreb
Faculty of Science
Department of Chemistry

Institutional repository: Repository of the Faculty of Science

Cite this document

Hloušek Kasun, A. (2023). Bakterijske i virusne makrodomene – struktura, funkcija i terapeutski potencijal (Doctoral thesis). Zagreb: University of Zagreb, Faculty of Science. Retrieved from https://urn.nsk.hr/urn:nbn:hr:217:629915

Hloušek Kasun, Andrea. "Bakterijske i virusne makrodomene – struktura, funkcija i terapeutski potencijal." Doctoral thesis, University of Zagreb, Faculty of Science, 2023. https://urn.nsk.hr/urn:nbn:hr:217:629915

Hloušek Kasun, Andrea. "Bakterijske i virusne makrodomene – struktura, funkcija i terapeutski potencijal." Doctoral thesis, University of Zagreb, Faculty of Science, 2023. https://urn.nsk.hr/urn:nbn:hr:217:629915

Hloušek Kasun, A. (2023). 'Bakterijske i virusne makrodomene – struktura, funkcija i terapeutski potencijal', Doctoral thesis, University of Zagreb, Faculty of Science, accessed 22 November 2024, https://urn.nsk.hr/urn:nbn:hr:217:629915

Hloušek Kasun A. Bakterijske i virusne makrodomene – struktura, funkcija i terapeutski potencijal [Doctoral thesis]. Zagreb: University of Zagreb, Faculty of Science; 2023 [cited 2024 November 22] Available at: https://urn.nsk.hr/urn:nbn:hr:217:629915

A. Hloušek Kasun, "Bakterijske i virusne makrodomene – struktura, funkcija i terapeutski potencijal", Doctoral thesis, University of Zagreb, Faculty of Science, Zagreb, 2023. Available at: https://urn.nsk.hr/urn:nbn:hr:217:629915

Metadata
TitleBakterijske i virusne makrodomene – struktura, funkcija i terapeutski potencijal
Title (english)Bacterial and viral macrodomains - structure, function and therapeutic potential
AuthorAndrea Hloušek-Kasun
MentorAndreja Mikoč (mentor)
MentorBranimir Bertoša (mentor)
Committee memberMarko Močibob (predsjednik povjerenstva)
Committee memberSanja Tomić (član povjerenstva)
Committee memberBranka Salopek-Sondi (član povjerenstva)
GranterUniversity of Zagreb
Faculty of Science
(Department of Chemistry)
Zagreb
Defense date and country2023-03-23, Croatia
Scientific / art field,
discipline and subdiscipline		NATURAL SCIENCES
Chemistry
Universal decimal classification
(UDC)		54 - Chemistry. Crystallography. Mineralogy
Abstract
ADP-ribozilacija je kovalentna modifikacija koja kontrolira brojne važne stanične procese od bakterija do čovjeka. ADP-ribozilacijski sustav čine ADP-ribozil-transferaze koje prenose ADPribozu na ciljnu (makro)molekulu i ADP-ribozil-hidrolaze koje osiguravaju reverzibilnost procesa. Glavni predstavnici ADP-ribozil-hidrolaza su makrodomenski proteini zastupljeni u sve tri domene života uključujući i viruse. U ovom doktorskom radu istraživana su dva makrodomenska proteina, SCO6735 iz bakterije Streptomyces coelicolor i Mac1 iz virusa SARS-CoV-2. Pokazano je da SCO6735 uklanja ADP-ribozilaciju s jednolančane DNA modificirane na timinu. Na temelju računalnih i eksperimentalnih rezultata predložen je novi katalitički mehanizam hidrolize ADPriboze s DNA karakterističan za skupinu proteina sličnih SCO6735. Makrodomena Mac1 inhibira imunološki odgovor domaćina čime potiče virusnu replikaciju. Stoga ima terapeutski potencijal za liječenje bolesti uzrokovane virusom SARS-CoV-2. U tu svrhu provedena je virtualna pretraga baze malih molekula koja je rezultirala testiranjem 27 spojeva metodom izotermalne titracijske kalorimetrije. Izmjereni afiniteti vezanja potvrdili su dobro vezanje nekoliko spojeva, uključujući FDA-odobrene lijekove Dasatinib i Metotreksat.
Abstract (english)
ADP-ribosylation is a covalent modification that controls essential cellular processes, conserved from bacteria to humans. The ADP-ribosylation system consists of ADP-ribosyl transferases that catalyse the transfer of ADP-ribose to a target (macro)molecule, while ADP-ribosyl hydrolases ensure reversibility. Macrodomain proteins are ADP-ribosyl hydrolases present in all three domains of life and viruses. In this dissertation, two macrodomain proteins were investigated: SCO6735 from Streptomyces coelicolor and Mac1 encoded by the virus SARS-CoV-2. SCO6735 was experimentally shown to act antagonistically to a bacterial toxin known to impair replication by ADP -ribosylation of thymidines in single-stranded DNA. Furthermore, a novel catalytic mechanism of DNA-(ADP-ribose) hydrolysis characteristic of the subgroup of SCO6735-related proteins was proposed. The Mac1 macrodomain is a good therapeutic target, because it inhibits the host immune response, thus allowing virus replication. In search of potential inhibitors, a virtual screening of a compound library was performed. The screening resulted in testing of 27 molecules with the isothermal titration calorimetry. Determined binding affinities suggested good binding of several molecules, including the FDA-approved drugs Dasatinib and Methotrexate.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:217:629915
Promotion2023
Study programmeTitle: Doctoral study in chemistry
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
Type of resourceText
ExtentXV, 134 str ; 30 cm
File originBorn digital
Access conditionsEmbargoed access
Embargo expiration date: 2024-11-23
Terms of useLicence In copyright icon
Created on2023-04-03 13:03:34