Advancing therapeutic and preventive strategies for combating coronaviruses: Small molecule antiviral drug discovery and development of methods to identify substandard/falsified vaccines

Thesis

An integrated approach combining both preventive and therapeutic strategies is essential for combating viral infections, including diseases caused by coronaviruses. The discovery of potent and specific antiviral drugs can significantly complement COVID-19 vaccine efforts but novel approaches are also needed to strengthen and safeguard both strategies. These include the development of small molecule inhibitors and innovative methods to detect substandard/falsified (SF) vaccines.

Currently, there is a shortage of potent oral antiviral drugs against SARS-CoV-2. Drug discovery efforts described in this study have led to the identification of three novel directly acting antivirals targeting the viral main protease, all showing strong inhibition of SARS-CoV-2 replication. In addition, the host-targeting antiviral iminosugar MON-DNJ demonstrated broad-spectrum activity against both SARS-CoV-2 variants and human coronavirus OC43. To address the threat of SF vaccines, new analytical methods have been developed to assist key shareholders in the future, including national regulatory authorities. Mass spectrometry (MS)-based techniques successfully distinguish genuine vaccines from counterfeit versions by analysing excipients. Furthermore, MALDI-ToF MS analysis of vaccine vial labels offers a non-invasive means of verifying authenticity. Simple low-cost assays also prove effective for detecting ethylene glycol and diethylene glycol contamination in raw materials and medicinal syrups, as well as for assessing heat-induced degradation in sucrose-containing vaccines via glucose detection.

Together, the advances in antiviral drug discovery and SF vaccine detection presented in this thesis provide critical tools to reinforce both therapeutic and preventive responses against corona- and other viruses. Their implementation could strengthen pandemic preparedness and improve future public health resilience.

Authors: Arman, Y

• DOI: 10.5287/ora-ga4pgved4
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: coronavirus; antiviral; mass spectrometry; COVID-19; drug discovery; substandard/falsified; MALDI-ToF; vaccine; supply chain; SARS-CoV-2
• Subjects: Virus; Coronavirus; Drug discovery; Medicine quality; Vaccine; COVID-19 vaccines; COVID-19 (Disease)