Imunostimulatorni i imunomodulatorni učinak derivata fenantridina

doctoral thesis

• Title (english): Immunnostimulatory and immunomodulatory potential of different phenanthridine derivatives
• Author: Natalija Knežević Teofilović
• Mentor: Nada Oršolić (mentor)
• Committee member: Jasmina Rokov Plavec (predsjednik povjerenstva)
• Committee member: Nada Oršolić (član povjerenstva)
• Committee member: Marijana Radić Stojković (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2017-07-10, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry
• Universal decimal classification (UDC): 54 - Chemistry. Crystallography. Mineralogy

Abstract

Toll-like receptori (TLR) sudjeluju u pokretanju prirođene i stečene imunosti. Fenantridini su heterociklički aromatski ugljikovodici čija struktura je slična strukturi nukleotidnih analoga koji su sintetski ligandi za TLR7 i TLR8. Poznati sintetski agonist TLR3 je analog dvostruke RNA (poli(I:C)), dok su TLR9 agonisti oligonukleotidi koji sadrže nemetilirane CpG dinukleotide (CpG-ODN). Istraživanja su pokazala da fenantridini imaju svojstvo ugradnje u strukture dvolančane DNA; potencijalno imunomodulatorno svojstvo.
U ovom istraživanju smo testirali 17 fenantridinskih derivata, pri čemu je spoj M-199 pokazao imunostimulacijski učinak. U ispitivanjima je pokazano da M-199 potiče izlučivanje IL-6, IL-8 i TNF-α, dok ne utječe na promjenu sadržaja IFN-α i IL-1β. Također smo pokazali da spoj M-199 ne djeluje preko TLR7 i TLR8. Tijekom ispitivanja međudjelovanja sa ligandima za TLR9 i TLR3, pokazano je da spoj M-199 ne utječe na stimulaciju TLR9 koja je posljedica vezanja liganda ODN2006, dok suprimira stimulaciju posredovanu ligandom ODN2216. M-199, također suprimira djelovanje poli(I:C).

Abstract (english)

Toll-like receptors (TLR) are responsible for activation and regulation of innate and adaptive immune response. Synthetic ligands activating TLR7 and TLR8 are nucleoside analogues resembling phenanthridine structure. Phenanthridines are heterocyclic aromatic hydrocarbons. Synthetic ligands for TLR3 are double-stranded RNA analogues (poly(I:C)) and ligands for TLR9 are oligonucleotides containing unmethylated CpG dinucleotide (CpG-ODN). Phenanthridine derivatives also intercalate in double-stranded DNA structure; having possible immunomodulatory potential.
In line with afore-mentioned we have tested 17 different phenanthridine derivatives and concluded that molecule M-199 shows immunostimulatory potential. In further analysis it was shown that M-199 stimulates synthesis of IL-6, IL-8 and TNF-α, while it has no effect on the levels of IFN-α and IL-1β. It was also shown that M-199 does not signal throught TLR7 or TLR8. The results of the interaction study indicated that M-199 does not interfere with ODN2009 while it interferes with ODN2216 and poli(I:C) showing suppression of stimulation.

• Keywords: fenantridini; imunomodulacijski potencijal; imunosni odgovor; TLR receptori
• Keywords (english): phenanthridines; immunomodulatory potential; immune response; TLR receptors
• Language: croatian
• URN:NBN: urn:nbn:hr:217:790463
• Study programme: Title: 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 resource: Text
• Extent: 122 str. ; 30 cm
• File origin: Born digital
• Access conditions: Open access
• Created on: 2017-07-26 11:40:14