De-Risking Non-Structural Protein 14 (NSP14) as a Novel Target for the Treatment of Human Coronaviruses

Three deadly coronavirus (CoV) infections have emerged in the last 20-years: SARS-CoV, MERS-CoV and the current SARS-CoV-2 pandemic. SARS-CoV-2 is the latest coronavirus to infect humans, and the resulting pandemic has created unprecedented challenges for healthcare systems around the world. While many of those infected have mild symptoms or are asymptomatic, the remaining individuals (often with underlying health conditions) encounter a more severe disease. This is characterised by significant respiratory symptoms, leading to acute respiratory distress syndrome and even death. Moreover so-called ‘long COVID’ has continued side effects long after infection, often causing debilitating impairment and multiple organ damage.
Efforts to design and produce vaccines have been successful and are widely available, and some small molecule therapeutics have been approved for use treating COVID-19. However, while vaccines need regular booster doses, novel small molecule therapeutics will continue to find important complimentary applications in addressing different stages of COVID-19 (the disease caused by SARS-CoV-2) disease presentation. This project will explore an innovative approach to treating past, present, and future coronaviruses.
One possible route to treat COVID-19 is to target the CoV-specific protein, non-structural protein 14 (NSP14). NSP14 is responsible for maintaining CoV replication fidelity, and in its absence CoV reproduction is severely affected. No marketed drug exists that targets NSP14, and there is evidence to suggest that inhibition could be a promising therapeutic strategy. The objective of this project is to synthesise and develop small molecules to selectively target NSP14, in order to create novel therapeutics for the treatment of human coronaviruses. Selected hit compounds taken from in-house and literature sources will be validated, assessed, and ultimately optimised for biochemical activity against NSP14 and for improved physicochemical properties.
Overall, this project has aimed to de-risk NSP14 as a novel target for human coronaviruses. This thesis has investigated inhibitors of both functional domains of NSP14. Although the exoribonuclease domain was found to have low druggability, high quality inhibitors of the methyltransferase domain were identified. Optimisation of this chemotype was carried out, aiming to improve the biochemical activity and physicochemical properties of the inhibitors. This yielded a series of potent inhibitors of NSP14, with excellent lead-like ADME profiles, in an attractive position for further optimisation for the treatment of human coronaviruses.