SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

Abstract Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated might lead to excessive inflammatory autoimmune responses as observed in severe long COVID-19 patients. Here we show that SARS-CoV-2 modulates reduces Accordingly, compound-driven induction of autophagy limits propagation. In detail, SARS-CoV-2-infected cells accumulation key metabolites, activation inhibitors (AKT1, SKP2) reduction proteins responsible for initiation (AMPK, TSC2, ULK1), membrane nucleation, phagophore formation (BECN1, VPS34, ATG14), well autophagosome-lysosome fusion ATG14 oligomers). Consequently, phagophore-incorporated markers LC3B-II P62 accumulate, which confirm a hamster model lung samples Single-nucleus single-cell sequencing patient-derived mucosal differential transcriptional regulation immune genes depending on cell type, disease duration, replication levels. Targeting autophagic pathways by exogenous administration the polyamines spermidine spermine, selective AKT1 inhibitor MK-2206, BECN1-stabilizing anthelmintic drug niclosamide inhibit propagation vitro with IC 50 values 136.7, 7.67, 0.11, 0.13 μM, respectively. Autophagy-inducing compounds reduce primary human intestinal organoids emphasizing their potential treatment options against COVID-19.