Targeting autophagy with natural products to prevent SARS-CoV-2 infection
Ontology highlight
ABSTRACT:
SUBMITTER: Vidoni C
PROVIDER: S-EPMC8516241 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), a β-coronavirus, is the cause of the recently emerged pandemic and worldwide outbreak of respiratory disease. Researchers exchange information on COVID-19 to enable collaborative searches. Although there is as yet no effective antiviral agent, like tamiflu against influenza, to block SARS-CoV-2 infection to its host cells, various candidates to mitigate or treat the disease are currently being investigated. Several drugs are being screened for the ability to block virus entry on cell surfaces and/or block intracellular replication in host cells. Vaccine development is being pursued, invoking a better elucidation of the life cycle of the virus. SARS-CoV-2 recognizes O-acetylated neuraminic acids and also several membrane proteins, such as ACE2, as the result of evolutionary switches of O-Ac SA recognition specificities. To provide information related to the current development of possible anti-SARS-COV-2 viral agents, the current review deals with the known inhibitory compounds with low molecular weight. The molecules are mainly derived from natural products of plant sources by screening or chemical synthesis via molecular simulations. Artificial intelligence-based computational simulation for drug designation and large-scale inhibitor screening have recently been performed. Structure-activity relationship of the anti-SARS-CoV-2 natural compounds is discussed.
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Project description:Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC<sub>50</sub> values of 136.7, 7.67, 0.11, and 0.13 μM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19.
2021-06-11 | MTBLS2840 | MetaboLights