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Callegaro, Sara (2017) G-quadruplexes in the herpes simplex virus type 1 and measles virus genomes: new antiviral targets. [Ph.D. thesis]

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Abstract (english)

G-quadruplexes (G4s) are four-stranded secondary structures formed by guanine-rich nucleic acids; they are implicated in important functions as epigenetic regulators at the genomic level in humans, prokaryotes and viruses. They act as silencers in the promoter regions of human genes and, moreover, they have been proposed to be directly involved in gene regulation at the transcription level.
Since the Herpes Simplex Virus Type 1 (HSV-1) genome is significantly rich in guanines (68%) and its G4 sequences are massively present during viral replication, we aimed at investigating the possibility to target the HSV-1 G4s by a core extended naphthalene diimide (c-exNDI) G4–ligand to obtain anti HSV-1 effects with an innovative mechanism of action.
Biophysical and biomolecular analysis proved that c-exNDI stabilized the HSV-1 G4s in a concentration-dependent manner and was able to inhibit Taq polymerase processing at G4 forming sequences. Additionally, we proved that c-exNDI preferentially recognized HSV-1 G4s over cellular telomeric G4s, the most represented G4s within cells. Treatment of HSV-1 infected cells with c-exNDI at low nanomolar concentrations induced significant virus inhibition with low cytotoxicity. The mechanism of action was ascribed to a G4-mediated inhibition of viral DNA replication, with consequent impairment of viral gene transcription.
Our data suggested that the observed potent antiviral activity and low cytotoxicity mainly depend on a combination of c-exNDI affinity for HSV-1 G4s and their massive presence during infection.
Since the vast majority of G4-ligands share the common characteristic of a large aromatic surface which makes them not well druggable, we then aimed at investigating the ability of an in-house library of compounds, previously designed to target promoters in cancer cells, to bind and stabilize HSV-1 G4s and to exert an antiviral activity against HSV-1. We demonstrated that all compounds of the library were able to bind and stabilize HSV-1 G4s in a concentration-dependent manner with different affinities and, again, to induce polymerase stalling because of a steric hindrance linked to the G4 stabilization. Treatment of HSV-1 infected cells with all compounds of the library showed a conspicuous decrease in viral production in the low nanomolar range. Two of the four compounds were also only mildly cytotoxic and thus showed promising selectivity indexes (SI). The mechanism of action, once again, was ascribed to the G4-mediated inhibition of viral DNA replication. Since all compounds of the library possess (i) promising chemical features (i.e their small size, smaller than other well known G4-ligands such as B-19 and NDIs) and (ii) potent activities in the low nanomolar range with no cytotoxicity, this makes them suitable for future development as novel anti HSV-1 G4-ligands with more drug-like characteristics than previous developed G4-ligands, and as promising compounds for the treatment of ACV-resistant herpetic infections.
In the third part of this study, by using a pull-down approach, we aimed at identifying viral and cellular proteins able to interact specifically with G4 structures within HSV-1 infected cells. We preliminarily identified both cellular and viral proteins directly implicated in replication and transcription processes. Concerning cellular proteins, we identified hnRNPU, nucleolin, nucleophosmin and histone proteins (11 and 12), some of them being already reported for their ability to bind G4s during replication. Identification of histone proteins opens the possibility that G4s are involved in the latent maintenance of the viral genome. Besides viral proteins we identified the transcription factor ICP4, the single-stranded DNA binding protein ICP8, PAP1 polymerase processing factor and VP5. The identification of the two transcription factors and of the polymerase processing factor confirmed the hypothesis of a direct involvement of G4s in the viral genome replication and transcription and the identification of the major capsid protein VP5 suggested a possible role of G4s as a driving force for viral genome encapsidation in the virions assembly process.
Finally, by investigating the negative-stranded RNA genome of Measles Virus (MV) we demonstrated the presence of seven G4-putative folding sequences. Six of these sequences displayed the ability to fold into G4 structures while one showed a hairpin-like conformation. All sequences were bound and stabilized by B-19 G4-ligand and treatment of MV infected cells with B-19 induced a pronounced reduction in the viral genome accumulation.
Since (i) G4s are well conserved and distributed within different viral genomes (as described by our group in HIV-1, HSV-1, and MV) because of their central roles in regulating biological processes and (ii) different G4-ligands have been demonstrated to be active against different viruses (i.e B-19, c-exNDI and G4-ligands of an in-house library in this thesis) with a G4-mediated inhibition of viral DNA replication, we can strongly encourage and confirm the hypothesis using G4s as novel broad range drug targets against different etiological agents and G4-ligands as novel innovative therapeutic molecules.

Abstract (italian)

I G-quadruplex sono strutture secondarie a quattro filamenti che possono essere formate all’interno di acidi nucleici ricchi nella composizione di guanine; i G-quadruplex sono implicati in importanti funzioni biologiche: questi agiscono come regolatori epigenetici a livello genomico in cellule umane, procariotiche e anche in virus.
I G-quadruplex agiscono come silenziatori a livello di regioni promotoriali in geni umani e, inoltre, sono stati riportati in letteratura per il loro diretto coinvolgimento nella regolazione dell’espressione genica.
Poiché il virus dell’Herpes Simplex di Tipo 1 (HSV-1) possiede un genoma caratterizzato da un’elevata percentuale di basi guanine (il 68%), e le strutture G-quadruplex identificate sono massivamente presenti durante la replicazione del virus stesso, abbiamo deciso di investigare la possibilità di agire direttamente su tali G-quadruplex attraverso l’utilizzo di un Naftalene Diimmide con core esteso (c-exNDI) per ottenere un’attività antivirale caratterizzata da un innovativo meccanismo d’azione.
Mediante caratterizzazione biofisica e biomolecolare abbiamo dimostrato che tale composto (c-exNDI) è in grado di stabilizzare sequenze G-quadruplex in modo concentrazione-dipendente e, ulteriormente è in grado di inibire il processamento della Taq polimerasi, in fase di elongazione del DNA, in corrispondenza delle strutture G-quadruplex.
Abbiamo inoltre dimostrato che il composto testato (c-exNDI) è in grado di riconoscere preferenzialmente i G-quadruplex virali rispetto ai G-quadruplex formati a livello delle regioni telomeriche che, all’interno di una cellula eucariotica, rappresentano i G-quadruplex maggiormente presenti. Il trattamento di cellule infettate con HSV-1 con il composto in analisi, utilizzato a basse concentrazioni, ha causato una significativa inibizione della produzione virale con parallela scarsa citotossicità sulle cellule. Infine, abbiamo dimostrato che il meccanismo d’azione di tale composto risiede nell’inibizione G-quadruplex-mediata della replicazione del DNA virale, con conseguente alterazione a valle della trascrizione genica.
Tali dati suggeriscono che la potente attività antivirale e la scarsa citotossità di tale composto dipendono principalmente da una combinazione di maggiore affinità del composto per i G-quadruplex virali e dalla loro massiccia presenza durante il processo di infezione.
Poiché la maggior parte dei composti leganti G-quadruplex è caratterizzata da un’ estesa superficie aromatica planare che li rende scarsamente farmaco-simili, ci siamo focalizzati sullo studio di una libreria di composti, precedentemente creata per agire sui G-quadruplex presenti nei promotori di oncogeni in cellule tumorali, al fine di valutare la capacità di tali composti di legare e stabilizzare i G-quadruplex presenti in HSV-1 e di esprimere un’attività antivirale diretta contro il medesimo virus. In questa parte di progetto abbiamo dimostrato che tutti i composti della libreria sono in grado di legare e stabilizzare i G-quadruplex virali secondo un meccanismo concentrazione-dipendente e, nuovamente, sono in grado di alterare la processività della polimerasi attraverso un ingombro sterico correlato alla formazione della struttura G-quadruplex.
Il trattamento di cellule infettate da HSV-1 con ciascuno dei composti della libreria a basse concentrazioni, ha mostrato una cospicua diminuzione della produzione virale. Poiché due dei quattro composti sono risultati scarsamente citotossici, per questi sono stati ottenuti promettenti indici di selettività (SI). Il meccanismo di azione di tali composti, come già visto in precedenza, è stato ascritto all’inibizione G-quadruplex-mediata della polimerasi in fase di replicazione del DNA virale.
Poiché tutti i composti della libreria sono caratterizzati da (i) strutture chimiche promettenti (dimensione più contenuta rispetto a quella di composti leganti G-quadruplex precedentemente sviluppati come BRACO-19 (B-19) e le Naftalene Diimmidi) e (ii) mostrano una potente attività contro HSV-1 a basse concentrazioni e una scarsa citotossicità, possono essere considerati composti fortemente adatti per lo sviluppo di nuovi farmaci leganti G-quadruplex contro HSV-1, e contro ceppi di HSV-1 resistenti al trattamento con Acyclovir (ACV), con caratteristiche fortemente farmaco-simili.
Nella terza parte del presente progetto di tesi, mediante un approccio di pull-down, abbiamo cercato di identificare proteine, sia cellulari che virali, in grado di interagire con strutture G-quadruplex presenti in cellule infettate. Risultati preliminari hanno portato all’identificazione di proteine sia cellulari che virali direttamente implicate in meccanismi di replicazione e trascrizione del genoma virale.
Per quanto riguarda le proteine cellulari, abbiamo identificato le proteine nucleari ribonucleoproteina U (hnRNPU), nucleolina, nucleofosmina e le proteine istoniche 11 e 12; alcune di queste proteine (hnRNP, nucleolina e nucleofosmina) erano già state riportate in letterature per la loro capacità di legare i G-quadruplex durante la replicazione della cellula. L’identificazione delle proteine istoniche 11 e 12 suggerisce la possibilità che le strutture G-quadruplex siano direttamente coinvolte nel mantenimento del genoma virale nel processo di latenza che tale virus è in grado di stabilire a livello di cellule del sistema nervoso centrale nell’uomo.
Tra le proteine virali abbiamo identificato il fattore di trascrizione ICP4, la proteina legante il DNA a singola catena ICP8, il fattore di processività della polimerasi PAP1 e la proteina capsidica VP5. L’identificazione delle proteine ICP4, ICP8 e PAP1, direttamente implicate in meccanismi di replicazione e trascrizione, conferma l’ipotesi di un diretto coinvolgimento delle strutture G-quadruplex nei meccanismi di replicazione e trascrizione del genoma virale. Inoltre, l’identificazione della proteina capsidica VP5 suggerisce la possibilità che le strutture G-quadruplex siano direttamente coinvolte nel processo di incapsidamento delle particelle virali neo-formate come guida per l’incapsidamento del genoma virale.
Infine, attraverso lo studio del genoma RNA a singolo filamento a polarità negativa del virus del Morbillo (MV), abbiamo dimostrato la presenza di sette sequenze caratterizzate da un’elevata probabilità di formare strutture G-quadruplex. Sei delle sette sequenze identificate hanno mostrato effettiva capacità di formare strutture secondarie G-quadruplex, mentre per una è stata dimostrata la capacità di formare una struttura secondaria a forcina. Tutte le sequenze hanno mostrato una stabilizzazione a seguito del legame con il composto B-19 e il trattamento delle cellule infettate ha mostrato una pronunciata riduzione nella sintesi del genoma virale.
In conclusione, dato che (i) le sequenze G-quadruplex sono fortemente conservate e distribuite in molteplici genomi virali (come ad esempio è stato dimostrato nel virus dell’Immunodeficienza Umano HIV-1, in HSV-1 e in MV) a causa della loro implicazione nella regolazione di diversi processi biologici, e (ii) diverse molecole leganti G-quadruplex (B-19, c-exNDI e piccole molecole di una libreria di composti) si sono dimostrate attive contro diversi virus attraverso un meccanismo di inizibione G-quadruplex-mediata della replicazione, possiamo confermare che le strutture G-quadruplex possono essere considerate come un ottimo bersaglio farmacologico per il trattamento di infezioni causate da diversi agenti eziologici e, inoltre, che piccole molecole in grado di legare e stabilizzare i G-quadruplex possono rappresentare innovativi farmaci con un nuovo meccanismo d’azione.

EPrint type:Ph.D. thesis
Tutor:Richter, Sara
Ph.D. course:Ciclo 30 > Corsi 30 > MEDICINA MOLECOLARE
Data di deposito della tesi:12 January 2018
Anno di Pubblicazione:31 October 2017
Key Words:G-quadruplex; Herpes Simplex Virus Type 1; Measles virus; Core Extended Naphthalene diimide compounds; Antiviral Activity
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/07 Microbiologia e microbiologia clinica
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:10739
Depositato il:26 Oct 2018 09:07
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