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Timmoneri, Martina (2018) Inhibition of HCMV replication by small molecules interfering with the dimerization of the DNA polymerase processivity factor UL44. [Ph.D. thesis]

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Abstract (italian or english)

Human cytomegalovirus (HCMV) is a leading cause of severe disease in immunocompromised individuals, including AIDS and transplanted patients, and in congenitally infected newborns. Despite the availability of several drugs, pharmacological treatment of HCMV infections is associated with poor bioavailability, toxicity and the emergence of resistant strains. Furthermore, no vaccine is available and no drugs are approved to prevent vertical transmission during pregnancy, therefore, it is essential to identify new potential targets of therapeutic intervention.

HCMV DNA polymerase accessory protein UL44 plays an essential role in viral replication, conferring processivity to the DNA polymerase catalytic subunit UL54 by tethering it to the DNA. Binding of UL44 to dsDNA occurs in the absence of ATP and clamp loaders, and depends on UL44 homodimerization. Indeed, our research group previously demonstrated that the protein can dimerize in cells and point mutations disrupting protein self-interaction also prevent DNA binding and abolish viral OriLyt-dependent DNA replication in transcomplementation assay. Therefore, disruption of UL44 homodimerization represents an attractive target for the development of new antivirals. Based on these observations, using the recently published crystal structure of UL44 hodimers our research group previously performed a virtual screening with the Glide software in combination with a library of 1.3 x 106 small molecules (SMs) to identify SMs potentially interfering with UL44 homodimerization. After three rounds of screening (HTVS: high-throughput virtual screening, SP: standard precision, XP: extra precision), followed by an in depth analysis of compounds chemical properties, 18 SMs were selected for further analysis. Selected compounds were obtained from a commercial supplier, to be tested in a variety of assays for their ability to inhibit UL44 homodimerization both in cell and in vitro, as well as on HCMV replication.

For this purpose, we applied two in vitro methods to monitor the effect of our candidates on UL44 dimerization such GST-pulldown Assay and Thermal Shift Assay (TSA). Furthermore, Plaque Reduction Assay (PRA) and Fluorescence Reduction Assay (FRA) were performed to study their inhibitory effects on viral replication.

Initially we validated that GST-pulldown assay was suitable to study UL44 dimerization and its perturbation caused by SMs. Therefore, we performed a first screening to test the effect of the 18 SMs on UL44 dimerization, and we identified 3 of these which reproducibly inhibited the dimerization. Prompted by these results, we selected such SMs to investigate a possible dose-response relationship between the dimerization inhibition and the compounds concentration. Unfortunately, data analysis revealed a high variability, and lack of correlation between the inhibition and the concentration of SMs used in the assays. In parallel, PRAs were performed to validate the effect of selected SMs, but these were unable to inhibit viral replication with high potency.

Subsequently, two recombinant HCMV viruses (TB4-IE2-EYFP and TB4-UL83-EYFP) were obtained from Michael Winkler (Leibniz-Institut für Primatenforschung Goettingen, Germany) in order to study the effect of our molecules on HCMV replication by FRAs. Therefore, after a screening of the 18 SMs, 4 of these were identified as possible inhibitors of viral replication and were selected to further studies. We investigated their and 50% effective dose (ED50) and 50% cytotoxic concentration (CC50) values and their effects on the viral gene expression. Only 2 SMs reproducibly inhibited expression of Early and Late genes.
Then we evaluated an alternative in vitro assay and among the various possibilities, we have chosen TSA that is able to inform whether a SM induce the disruption of constitutive oligomeric interfaces. In a first moment we validated that the assay allow the discrimination between monomeric and dimeric forms of UL44, suggesting its potential for the screening of our SMs. As result of the SMs screening by TSA, one molecule revealed a possible inhibition of dimerization.

Abstract (a different language)

Cytomegalovirus (CMV) è un importante patogeno di interesse umano. Al momento gli antivirali disponibili ed utilizzati per la terapia contro l’infezione da CMV presentano una serie di problematica quali l’alto costo, bassa biodisponibilità, alta tossicità ed il presentarsi di ceppi virali resistenti. Inoltre non è disponibile un vaccino ed ancora non è stato approvato alcun farmaco per prevenire la trasmissione verticale durante la gravidanza. Per questi motivi, sono necessari nuovi efficaci farmaci antivirali.

La proteina accessoria UL44 della DNA polimerasi di CMV, svolge un ruolo essenziale nella replicazione virale, conferendo processività alla subunità catalitica UL54 ancorando il complesso oloenzimatico al DNA.
Il legame di UL44 al dsDNA avviene in assenza di ATP e dei clamp loaders, e dipende dalla omodimerizzazione di UL44. Il nostro gruppo di ricerca, infatti ha recentemente dimostrato che la proteina può dimerizzare in cellule e che mutazioni puntiformi in grado di inficiare tale dimerizzazione prevengono il legame con il DNA ed aboliscono la replicazione del DNA virale oriLyt-dipendente in saggi di transcomplementazione transiente.
Perciò, la distruzione dell’omodimerizzazione UL44 rappresenta un potenziale ed allettante target per lo sviluppo di nuovi antivirali. Partendo da queste osservazioni ed usando la struttura cristallografica degli omodimeri UL44 che è stata recentemente pubblicata, il nostro gruppo di ricerca ha eseguito un virtual screening con il software Glide in combinazione con una libreria di 1.3 x 10^6 piccole molecole (SMs) per identificare SMs che potenzialmente potessero interferire con l’omodimerizzazione di UL44. Dopo tre rounds di screening (HTVS: high-throughput virtual screening, SP: standard precision, XP: extra precision), seguiti da un’analisi delle proprietà chimiche dei composti, sono state selezione 18 SM per ulteriori analisi. I composti selezionati sono stati acquistati presso un fornitore commerciale, per essere testati in diversi saggi per valutare le loro abilità di inibire l’omodimerizzazione di UL44 in vitro, sia la replicazione virale.

Con questo scopo, abbiamo utilizzato due metodi in vitro per monitorare l’effetto dei nostri candidati sulla dimerizzazione di UL44, quali GST-pulldown assay e Thermal Shift Assay (TSA). Inoltre per studiare l’inibizione sulla replicazione virale sono stati eseguiti saggi di Plaque Reduction Assay (PRA) e Fluorescence Reduction Assay (FRA).

Inizialmente abbiamo confermato che il GST-pulldown assay fosse idoneo per studiare la dimerizzazione di UL44 e la sua perturbazione causata dalle SMs. Pertanto abbiamo eseguito un primo screening per saggiare l’effetto delle 18 SMs sulla dimerizzazione di UL44, ed abbiamo identificato 3 molecole che inibivano la dimerizzazione in modo riproducibile. Incoraggiati da questi risultati, abbiamo selezionato queste SMs per valutare una possibile relazione dose-risposta tra l’inibizione della dimerizzazione e la concentrazione dei composti. Sfortunatamente, l’analisi dei dati hanno rivelato alta variabilità, e perdita di correlazione tra l’inibizione e la concentrazione delle SMs utilizzate nei saggi.
In parallelo, abbiamo eseguito PRAs per validare l’effetto delle SMs precedentemente selezionate, ma queste si sono presentati incapaci di inibire la replicazione virale in modo consistente.

Successivamente abbiamo ottenuto due virus CMV ricombinanti (TB4-IE2-EYFP and TB4-UL83-EYFP) da Michael Winkler (Leibniz-Institut für Primatenforschung Goettingen, Germany) per studiare l’effetto delle nostre molecole sulla replicazione di CMV mediante FRAs. Pertanto, dopo uno screening delle 18 SMs, 4 di queste sono state identificate come possibili inibitori della replicazione virale e sono state selezionate per essere ulteriormente studiate. Abbiamo valutato la loro dose effettiva 50% (ED50) e la loro concentrazione citotossica 50% (CC50) e gli effetti relativi all’espressione genica. Solo due SMs in modo riproducibile inibivano l’espressione dei geni Early e Late.

Poi abbiamo valutato un saggio in vitro alternativo e tra le varie possibilità, abbiamo scelto il TSA che è un saggio in grado di informare se una SM induce la distruzione delle interfacce di un oligomero costitutivo. In un primo momento abbiamo confermato che il saggio permettesse la discriminazione tra le forme monomeriche e dimeriche di UL44, suggerendo il suo potenziale per lo screening delle nostre SMs. Come risultato di questo screening, una molecola ha rivelato possibile inibizione della dimerizzazione.

EPrint type:Ph.D. thesis
Tutor:Alvisi, Gualtiero
Ph.D. course:Ciclo 31 > Corsi 31 > MEDICINA MOLECOLARE
Data di deposito della tesi:28 November 2018
Anno di Pubblicazione:2018
Key Words:HCMV, inibizione replicazione virale, piccole molecole, interazione proteina-proteina / inhibition of viral replication, small molecules, protein-protein interaction.
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/19 Microbiologia generale
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:11433
Depositato il:06 Nov 2019 12:10
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