The design and synthesis of antiviral compounds that target human Coronaviruses

Outteridge, Mia

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Outteridge, Mia (2026) The design and synthesis of antiviral compounds that target human Coronaviruses. Doctoral thesis, London Metropolitan University.

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Abstract

Introduction and Aim:
A need for broadly functional human coronavirus (CoV) antivirals exists. The aim of this study is to synthesise antiviral chemical compounds that target conserved functions of CoV replication and would therefore be applicable to numerous CoVs including future outbreaks as well as other pathogenic infections with similar genetic properties.

Research Methods and Results:
Bioinformatic studies have identified a conserved region across the 7 HCoVs using a multiple sequence alignment and analysis of the genomes. NSP3 was identified as the main target because of its conserved roles across the HCoVs. A lead compound was identified by searching libraries of known small molecules that bind to and interrupt CoV viral replication in vitro. Alterations were made to the lead compound's molecular structure by replacing different functional groups to further improve binding and its antiviral properties. There were 3 series of drugs proposed, including benzene, naphthalene and quinoline derivatives and chlorine, fluorine, trifluoromethane and methoxyl functional groups which are proposed to bind to pan-CoVs including future emergences. Docking studies were completed which showed quinoline-containing compounds generating the lowest ΔG energy towards the NSP3, indicating it has improved binding properties. The other compounds also proved to have a successful binding affinity compared to the lead compound, and all compounds were synthesised and purified. Most compounds showed no signs of cytotoxicity in LLC-MK2 and VeroE6-ACE2-TMPRSS2 cell lines, and even though there were no antiviral effects in CoV-OC43, 1-[1-(quinolin-4-yl)ethyl]-N-{[3(trifluoromethyl)phenyl]methyl}piperidine-4-carboxamide (compound 28) showed statistically significant evidence of antiviral activity against CoV-NL63, a very positive outcome for novel compounds.

Conclusion and Future Work:
As a result of successful docking of novel compounds and in vitro synthesis, compound 28 showed some positive effects in CoV-NL63. Further confirmatory assays are in future works to provide more evidence of the binding between the compound and NSP3, which is a great contribution to the development of an antiviral that may be repurposed to other CoVs if given the opportunity as well as future CoVs and other pathogens.

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