Broad-spectrum antivirals against coronavirus using natural products and drug repurposing strategies

The COVID-19 pandemic has highlighted the critical need for broad-spectrum antiviral therapeutics capable of addressing current and future viral outbreaks. Coronaviruses, particularly SARS-CoV-2, continue to pose significant public health threats due to their zoonotic origin, adaptability, and rapid spread. While vaccines and virus-specific antivirals have been developed, emerging variants and novel pathogens underscore the importance of developing therapeutics with broader applicability. This thesis explores a dual strategy to expand the antiviral toolkit: natural product-based discovery and host-targeted drug repurposing. Chapter three investigates natural product-based antiviral discovery, with a focus on Nigella sativa (black seed) oils. While direct contact assays revealed limited antiviral efficacy, vapour-phase diffusion of the oils significantly reduced coronavirus infectivity. Chemical analysis identified volatile terpenes and phenolic compounds—particularly TQ—as key antiviral constituents. These volatile agents exhibited selective activity against enveloped viruses, likely through virion envelope disruption, highlighting an underexplored mechanism of antiviral action via inhalable phytochemicals. Chapter four expands this investigation to direct-contact antivirals from other medicinal plants, screening purified compounds with known ethnopharmacological relevance. Several phytochemicals exhibited activity against OC43 and HCoV-229E, with select compounds demonstrating low cytotoxicity and promising antiviral profiles. Chapter five shifts to host-targeting strategies through the repurposing of PROTACs (Proteolysis-Targeting Chimeras). Originally developed for oncology, these bifunctional molecules were assessed for their ability to degrade key host proteins exploited by coronaviruses during replication and entry. Select PROTACs targeting kinases such as p38 MAPK and CDK6 demonstrated antiviral activity in vitro using BSL-2-compatible seasonal coronavirus models and SARS-CoV-2 pseudotyped lentiviruses, supporting their potential as a novel class of host-directed antivirals. Together, these chapters demonstrate the feasibility of both natural product vapours and host-targeted protein degraders as complementary antiviral strategies. By integrating classical plant-based approaches with innovative drug repurposing tools, this work provides proof-of-concept for the development of novel, broad-spectrum antiviral therapeutics. These findings support the need for continued investment in alternative antiviral strategies that are adaptable, accessible, and effective against a range of viral threats.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

De Montfort University

Year dc:date.issued

2025

Author dc:creator

• Cooper, Gemma

Licence

• https://dora.dmu.ac.uk/bitstreams/083eb609-9aff-413b-a377-25ebad83ad50/download