Pharmacological inhibition of coronavirus replication via modulation of host lipid metabolism

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 and the subsequent coronavirus disease 2019 pandemic highlighted the urgent need for novel therapeutic approaches. Coronaviruses rely extensively on host cell metabolic pathways to support their propagation, and efficient viral replication requires the extensive remodelling of host cell membranes. This includes the formation of specialized membranous structures known as replication organelles that accommodate viral RNA synthesis in the cytoplasm of the infected cell. Other processes depending on host membranes are viral entry, the acquisition of the coronavirus envelope from intracellular membrane compartments and the post-translational conjugation of lipids to certain viral proteins. The endogenous pathways involved in these pivotal steps of coronavirus replication represent attractive targets for host-directed antiviral therapy, which may also reduce the emergence of resistance that often limits the efficacy of direct-acting antiviral drug treatment. Accordingly, recent studies have identified a range of small-molecule inhibitors that target lipid metabolism pathways and display promising antiviral activity against coronaviruses. In this review, we examine the pharmacological modulation of lipid metabolism with small-molecule inhibitors as an antiviral strategy against SARS-CoV-2 and other coronaviruses and discuss the strengths, limitations and translational challenges associated with these compounds. We further consider how advances in our understanding of such virus–host metabolic interactions may facilitate the development of broadly active host-directed antivirals, contributing to pandemic preparedness against known and newly emerging coronaviruses.