Cottignies-Calamarte Andrea, Marteau Flora, He Feifan, Belouzard Sandrine, Dubuisson Jean, Tudor Daniela, Viollet Benoit, Bomsel Morgane
Laboratory of Mucosal Entry of HIV and Mucosal Immunity Institut Cochin, Paris, France.
Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France.
J Virol. 2025 Jun 12:e0039425. doi: 10.1128/jvi.00394-25.
AMP-activated protein kinase (AMPK) plays a central role in regulating cell energy balance. When activated, AMPK suppresses energy-consuming pathways, such as lipid and protein synthesis, while increasing nutrient availability through the activation of autophagy. These pathways downstream of AMPK activation contribute to SARS-CoV-2 infection, which hijacks autophagy and accumulates lipid droplets in viral factories to support viral replication. Here, we assessed the antiviral activity of the direct pan-AMPK allosteric activator MK-8722 . MK-8722 efficiently inhibited infection of Alpha and Omicron SARS-CoV-2 variants in Vero76 and human bronchial epithelial Calu-3 cells at micromolar concentration. This inhibition relied on restoring the autophagic flux, which redirected newly synthesized viral proteins for degradation, and reduced lipid metabolism, which affected viral factories. Furthermore, MK-8722 treatment increased the type I interferon (IFN-I) response. Post-infection treatment with MK-8722 was enough to inhibit efficient viral replication and restore the IFN-I response. Finally, MK-8722 treatment did not alter the SARS-CoV-2-specific CD8 T cell response mounted upon Spike vaccination. Overall, by activating AMPK, MK-8722 acts as an effective antiviral against SARS-CoV-2 infection, even when applied post-exposure, paving the way for preclinical tests aimed at inhibiting viral replication and improving patients' symptoms.
Coronavirus disease 2019, caused by SARS-CoV-2 infection, has led to severe acute respiratory syndrome with very high mortality. Despite available vaccines and public health measures, new SARS-CoV-2 variants emerge with increased transmissibility requiring the development of novel therapeutic strategies. Recently, the AMP-activated protein kinase (AMPK), a cellular energy sensor, has emerged as a potential broad-spectrum antiviral target, as AMPK can modulate the intracellular environment in turn impeding viral replication. This study aims to evaluate the potential of pharmacological activation of AMPK to inhibit SARS-CoV-2 infection and replication. Our findings demonstrate that AMPK activation induces significant alterations in host cellular lipid metabolism that disrupt viral factories essential for SARS-CoV-2 replication. Furthermore, by enhancing autophagy, a process crucial for the degradation and clearance of viral particles, AMPK activation facilitates the elimination of the virus. Therefore, targeting AMPK signaling pathways could offer a promising therapeutic approach for the treatment of SARS-CoV-2 infections.
AMP激活的蛋白激酶（AMPK）在调节细胞能量平衡中起核心作用。激活后，AMPK会抑制脂质和蛋白质合成等耗能途径，同时通过激活自噬增加营养物质的可利用性。AMPK激活后的这些途径有助于严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染，该病毒会劫持自噬并在病毒工厂中积累脂滴以支持病毒复制。在此，我们评估了直接的泛AMPK变构激活剂MK-8722的抗病毒活性。MK-8722在微摩尔浓度下能有效抑制Vero76细胞和人支气管上皮Calu-3细胞中Alpha和奥密克戎SARS-CoV-2变体的感染。这种抑制作用依赖于恢复自噬通量，自噬通量会将新合成的病毒蛋白重新导向降解，并减少脂质代谢，脂质代谢会影响病毒工厂。此外，MK-8722处理增强了I型干扰素（IFN-I）反应。感染后用MK-8722处理足以抑制有效的病毒复制并恢复IFN-I反应。最后，MK-8722处理并未改变接种刺突蛋白疫苗后产生的SARS-CoV-2特异性CD8 T细胞反应。总体而言，通过激活AMPK，MK-8722可作为一种有效的抗SARS-CoV-2感染药物，即使在接触后应用也有效，为旨在抑制病毒复制和改善患者症状的临床前试验铺平了道路。
由SARS-CoV-2感染引起的2019冠状病毒病导致了死亡率极高的严重急性呼吸综合征。尽管有可用的疫苗和公共卫生措施，但新出现的SARS-CoV-2变体传播性增加，需要开发新的治疗策略。最近，AMP激活的蛋白激酶（AMPK）作为一种细胞能量传感器，已成为潜在的广谱抗病毒靶点，因为AMPK可以调节细胞内环境，进而阻碍病毒复制。本研究旨在评估通过药物激活AMPK来抑制SARS-CoV-2感染和复制的潜力。我们的研究结果表明，AMPK激活会诱导宿主细胞脂质代谢发生显著变化，从而破坏SARS-CoV-2复制所必需的病毒工厂。此外，通过增强自噬（这是病毒颗粒降解和清除的关键过程），AMPK激活促进了病毒的清除。因此，靶向AMPK信号通路可能为治疗SARS-CoV-2感染提供一种有前景的治疗方法。
