Synthetic cyclonucleosides as potential anti-viral agents and glycosyltransferase inhibitors

Abstract

Modified nucleosides and their derivatives have emerged as a versatile class of anti-viral, anti-microbial, anti-cancer molecules. Cyclonucleosides are strained, hydrophobic, modified nucleosides that can be exploited to develop new therapies.

Well-established research on nucleosides indicates their potential anti-viral activity. This activity is attributed to their structural similarity with native nucleosides and competitively inhibiting their activity. This suggests that cyclonucleosides may also act as anti-viral agents.

Previous studies by the Wagner research group indicate that C5 of nucleoside is essential for glycosyltransferase activity. Glycosyltransferases (GTs) play a role in normal cellular functions and in bacterial and viral infections. Therefore, a substitution on the C5 of the cyclonucleosides leads to a hybrid molecule with GT inhibitory activity.

The overall goal of this project is to understand the effect of these hybrid 5-substituted cyclonucleosides on rhinovirus-infected cells and GTs. This was achieved using computational and biological approaches. Cyclonucleosides and their corresponding nucleoside analogues were synthesised using the Suzuki coupling reaction and cyclisation reactions.

Our collaborators from WWIEM performed a viral titre TCID50 assay for all the synthesised cyclonucleosides. At 500 μM concentration, 4B (88.1 μM), 8B (43.1 μM), 11A (90.6 μM) and 14B (101.2 μM) were identified as lead compounds against rhinovirus RV A-16 strain. 8B exhibited an IC50 close to the positive control, 7DMA (10 μM). Molecular docking of 3DPol of rhinovirus and poliovirus suggests that π-π stacking and π-cation interactions may result in anti-viral activity.

The hybrid 5-substituted cyclonucleosides were tested against β1,4-GalT7 by our collaborators from Lund University, Sweden. 5A displayed 100% inhibition and molecular modelling was performed on the 5A- β1,4-GalT7 complex to study the interactions responsible for activity. Additionally, an extensive conformational analysis was performed to identify the bioactive conformation of nucleosides and nucleotides, assisting in other target identification.

Thesis is embargoed until 31st December 2025.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Ministry of Social Justice and Empowerment, India
Supervisor	Gerd Wagner (Supervisor) & Irina Tikhonova (Supervisor)