The pandemic potential of RNA viruses is well known, as demonstrated by the recent COVID-19 outbreak, however available therapeutic options to treat related viral infections are limited. Therefore, there is an urgent need to identify, develop, and stockpile new small-molecule therapeutics with broad antiviral coverage against currently known pathogenic RNA virus families, for pandemic preparedness and prevention. Nucleoside analogues (NAs) are synthetic compounds that utilize the same metabolic pathways as endogenous nucleosides and undergo incorporation into RNA (or DNA), thereby effectively inhibiting viral replication. However, NAs must be activated to their triphosphate form to exert their activity, but often are poor substrates for kinases. Especially, the first phosphorylation is regarded as the rate-limiting step in the nucleoside activation cascade and the cause for hindering therapeutic efficiency. Therefore, prodrugs are frequently designed to deliver nucleoside monophosphate intracellularly. This thesis focused on the synthesis and antiviral evaluation of phosphoroamidate prodrugs (or ProTides) of base-modified 7-deazapurine ribonucleoside, which were previously shown to possess promising in vitro activities against Tacaribe virus (TCRV). TCRV is a low virulence virus closely related to highly pathogenic species of the same family, like choriomeningitis-Lassa (LCMV) and Junin virus (JUNV), which is useful to study the link between arenavirus infections and related diseases. The synthesis of the targeted base-modified ribonucleosides was achieved using palladium-catalysed chemistry as key step to insert different substituents at the 6-position of 7-deazapurine, while the coupling with a phosphorochloridate reagent successfully delivered the desired prodrugs. The final products were purified by HPLC reverse-phase chromatography, while all intermediate and final compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analyses.

Synthesis and antiviral evaluation of base-modified ribonucleoside prodrugs against Tacaribe virus

GUADAGNO, LUDOVICA
2022/2023

Abstract

The pandemic potential of RNA viruses is well known, as demonstrated by the recent COVID-19 outbreak, however available therapeutic options to treat related viral infections are limited. Therefore, there is an urgent need to identify, develop, and stockpile new small-molecule therapeutics with broad antiviral coverage against currently known pathogenic RNA virus families, for pandemic preparedness and prevention. Nucleoside analogues (NAs) are synthetic compounds that utilize the same metabolic pathways as endogenous nucleosides and undergo incorporation into RNA (or DNA), thereby effectively inhibiting viral replication. However, NAs must be activated to their triphosphate form to exert their activity, but often are poor substrates for kinases. Especially, the first phosphorylation is regarded as the rate-limiting step in the nucleoside activation cascade and the cause for hindering therapeutic efficiency. Therefore, prodrugs are frequently designed to deliver nucleoside monophosphate intracellularly. This thesis focused on the synthesis and antiviral evaluation of phosphoroamidate prodrugs (or ProTides) of base-modified 7-deazapurine ribonucleoside, which were previously shown to possess promising in vitro activities against Tacaribe virus (TCRV). TCRV is a low virulence virus closely related to highly pathogenic species of the same family, like choriomeningitis-Lassa (LCMV) and Junin virus (JUNV), which is useful to study the link between arenavirus infections and related diseases. The synthesis of the targeted base-modified ribonucleosides was achieved using palladium-catalysed chemistry as key step to insert different substituents at the 6-position of 7-deazapurine, while the coupling with a phosphorochloridate reagent successfully delivered the desired prodrugs. The final products were purified by HPLC reverse-phase chromatography, while all intermediate and final compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analyses.
2022
Synthesis and antiviral evaluation of base-modified ribonucleoside prodrugs against Tacaribe virus
Prodrug
Ribonucleoside
Tacaribe virus
File in questo prodotto:
File Dimensione Formato  
Tesi_Guadagno_Ludovica.pdf

accesso riservato

Dimensione 1.6 MB
Formato Adobe PDF
1.6 MB Adobe PDF

The text of this website © Università degli studi di Padova. Full Text are published under a non-exclusive license. Metadata are under a CC0 License

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12608/43074