AMP-activated protein kinase (AMPK) plays a central role in regulating cellular energy balance. When activated, AMPK suppresses energy-consuming pathways, such as lipid and protein synthesis, while increasing nutrient availability by activating the process of waste degradation and recycling within the cell (autophagy).
In infected cells, the SARS-CoV-2 virus hijacks autophagy and accumulates lipid droplets in viral factories, which sustain viral replication. Targeting AMPK could represent a novel antiviral therapeutic strategy. Indeed, AMPK activation could impede viral replication by modulating the intracellular environment.
The MK-8722 molecule is a specific activator of AMPK. Morgane Bomsel's team (Institut Cochin), in collaboration with Benoit Viollet (Institut Cochin) and Jean Dubuisson's team (Pasteur Institute of Lille), evaluated the antiviral activity of MK-8722 in vitro. In these studies, MK-8722 effectively inhibits infection of the Alpha and Omicron variants of SARS-CoV-2 in Vero76 model epithelial cells and Calu-3 human bronchial epithelial cells at a micromolar concentration. This inhibition is based on the restoration of autophagic flux, which redirects newly synthesized viral proteins to degradation, as well as on the reduction of lipid metabolism, which affects the viral factories that facilitate virus clearance.
Furthermore, treatment with MK-8722 increases the response to type I interferon (IFN-I). MK-8722 treatment is not only effective during infection but also up to 4 hours post-infection, inhibiting viral replication and restoring the IFN-I response.
Finally, MK-8722 treatment does not diminish and even slightly increases the SARS-CoV-2-specific CD8+ T cell response induced by Spike protein vaccination. MK-8722 may thus enhance the SARS-CoV-2-specific CD8+ T cell response at the site of infection.
By activating AMPK, MK-8722 acts as an effective antiviral against SARS-CoV-2 infection, even after exposure, paving the way for preclinical trials aimed at inhibiting viral replication and improving patient symptoms.
Reference
Andrea Cottignies-Calamarte, Flora Marteau, Feifan He, Sandrine Belouzard, Jean Dubuisson, Daniela Tudor, Benoit Viollet, Morgane Bomsel. Direct pharmacological AMPK activation inhibits mucosal SARS-CoV-2 infection by reducing lipid metabolism, restoring autophagy flux, and the type I IFN response. J. Virol 2025; 0:e00394-25. https://doi.org/10.1128/jvi.00394-25
