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Giaretta, Giulia (2008) Acidi nucleici come target terapeutici nello sviluppo di composti antivirali o antiproliferativi. [Tesi di dottorato]

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Abstract (inglese)

Nucleic acids represent a good target for the development of new drugs, whose mechanism of action can be related to the inhibition of nuclear functions, both through a direct interaction with DNA or RNA, or by interference with enzymatic or not enzymatic elements fundamental for the replication and transcription of the nucleic acids.
In this thesis we analyzed the activity of potential antiviral or antitumoral drugs, whose therapeutic targets are represented by viral or cellular nucleic acids, alone or in complex with proteins.
An attractive target for the development of new antiviral agents against HIV-1 is the interaction between Tat and TAR. Tat (transactivator of transcription), is a small HIV protein rich in arginines essential for viral gene expression, replication and pathogenesis. Tat requires specific interactions with TAR (trans-activation responsive region), a short RNA structure located at the 5' ends of all nascent HIV-1 transcripts. Small molecules able to interfere with TAR and to compete for Tat binding would possess antiviral activity due to inhibition of viral transcription and expression, resulting in non-assembly of mature functional virions.
The goal of our first research is the study of compounds able to interfere with the viral phase of trans-activation. To this aim we have analyzed two series of 2-phenylquinolones (series WRNA), synthesized by the group of Prof. Cecchetti and Prof. Tabarrini of the University of Perugia. These new compounds are designed rationally with the aim of binding the TAR bulge thus interfering with Tat-TAR complex formation.
To evaluate the interference toward the Tat/TAR complex of the novel quinolones, we have developed a Fluorescence Quenching assay (FQA). The FQA protocol envisages the use of a nucleic acid labelled with a quencher moiety (Q) and of a peptide labelled with a fluorescence dye (F). In particular we have used a RNA-TAR labelled with the quencher dabcyl and the sequence of the core of Tat labelled with the donor fluorescein at its N-terminal. The fluorescence is high when the macromolecule is free in solution, but emission dramatically decreases when the fluorophore is in close proximity to the quencher molecule (i.e. when the Tat-TAR complex is formed), thus allowing to quantify the extent of complex formation. With this FQ assay we have been able to study the inhibition of Tat/TAR complex formation, i.e. to discriminate the WRNA quinolones with an inhibitory activity comparable or better than the positive control WM5, from the compounds that are weaker competitors of peptide/RNA complex. The results obtained for the first serie of phenylquinolones were consistent with those obtained by gel shift analysis (EMSA): this classic electrophoresis assay confirmed the ability of some new compounds to distrupt the complex in vitro.
We have then evaluated the binding affinities of the compounds toward TAR either wild type or mutant; mutants were designed to discriminate the relative contribution to binding by the different substructures of the nucleic acid (stem, loop, bulge); an RNA sequences not related to TAR (tRNA) and DNA, both single and double strand were also analyzed. The binding affinity of the first series quinolones toward nucleic acids was evaluated by equilibrium dialysis measurements.
Finally we have estimated the antiviral activity of these basic compounds, their cytotoxicity by MTT assay and their cell penetration by uptake studies with different cell lines and protocols.
The compounds of the first series that emerged as mostly active led to the synthesis of a second series of 2-phenylquinolones. The effect of the designed substitutions on quinolone rings on activity, tested by FQ assay, cytotoxicity and cell penetration has allowed us to delineate a more precise structure-activity relationship (SAR), useful to direct further synthesis of active compounds.
The Fluorescence Quenching assay used for testing the interfering with Tat-TAR complex represent a protocol for HTS (High Throughput Screening) analysis to efficiently test library of potential inhibitors. Therefore we have tested other classes of compounds beside the WRNA series. In particular we have evaluated the activity of some of 6-aminoquinolone derivatives, a small serie of acridone derivatives and some anthraquinones with one or two peptide chains at position 2 and/or 6.
With this first screening we have been able to identify very active compounds, and have gotten further indications related to the interaction from the molecules with the RNA-TAR and the implication for Tat inhibition.
The second project aimed at cellular DNA sequences hence at possible anticancer goals, we have analyzed the sequence specificity of DNA binding of a new series of peptidyl-anthraquinones synthesized according to the modelling studies of Prof. Gresh of the University of Paris; these theoretical studies suggested that tailor made drug peptide conjugates can be properly designed to target specific base pairs arrangements.
Therefore we describe here the DNA binding characteristic and cellular activity of a series of compounds in which the planar anthraquinone chromophore fused to the side chains of ametantrone or to other bioisosteric linkers has been conjugated to simple peptidyl chains. Peculiarity of these peptide derivatives of ametantrone stands in the selective binding to important palindromic sequences, as the sequence d(CCCGGG)2, located in several oncogenes and in HIV-1 LTR.
To evaluate the intercalating power of the novel compounds, we have used the unwinding assays. Then, the attention is turned to a assay more sensitive to study the sequence specificity: by the use of appropriate FRET (Fluorescence Resonance Energy Transfer) probes devised according to modelling studies we have demonstrated the sequence-specific properties of the novel designed compounds and thus validate the theoretical predictions.
To this point, once validate the theoretical predictions about the specificity of sequence, we have estimated the effect of the new molecules on Topoisomerase II, an enzyme target of many antineoplastic agents, that acts on the DNA. Particularly we have tested two different types of enzymatic activity: the decatenation and the relaxation of the plasmid DNA.
Finally we have examined the cytotoxicity and the potentiality of the drugs to cross the cellular membranes through experimental calculation of the partition coefficient.
The results obtained by these last studies, with the encouraging data of selectivity of sequence of some compounds, give useful indications to address the synthesis of new active derivatives with high specificity toward oncogenic sequences.


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Tipo di EPrint:Tesi di dottorato
Relatore:Gatto, Barbara
Dottorato (corsi e scuole):Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MOLECOLARI > SCIENZE FARMACEUTICHE
Data di deposito della tesi:31 Gennaio 2008
Anno di Pubblicazione:31 Gennaio 2008
Parole chiave (italiano / inglese):Tat-TAR, Transattivazione, Chinoloni, Peptidil-Antrachinoni, Sequenza-specifico
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Farmaceutiche
Codice ID:549
Depositato il:24 Ott 2008
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