Evaluation of the Cytotoxic and Antiviral Effects of Small Molecules Selected by In Silico Studies as Inhibitors of SARS-CoV-2 Cell Entry.
Francisca CarvalhalAna Cristina MagalhãesRita RebeloAndreia PalmeiraDiana I S P ResendeFernando DurãesMiguel MaiaCristina P R XavierLuísa PereiraMaria Emília SousaMarta Correia-da-SilvaMaria Helena VasconcelosPublished in: Molecules (Basel, Switzerland) (2023)
The spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) relies on host cell surface glycans to facilitate interaction with the angiotensin-converting enzyme 2 (ACE-2) receptor. This interaction between ACE2 and the spike protein is a gateway for the virus to enter host cells and may be targeted by antiviral drugs to inhibit viral infection. Therefore, targeting the interaction between these two proteins is an interesting strategy to prevent SARS-CoV-2 infection. A library of glycan mimetics and derivatives was selected for a virtual screening performed against both ACE2 and spike proteins. Subsequently, in vitro assays were performed on eleven of the most promising in silico compounds to evaluate: (i) their efficacy in inhibiting cell infection by SARS-CoV-2 (using the Vero CCL-81 cell line as a model), (ii) their impact on ACE2 expression (in the Vero CCL-81 and MDA-MB-231 cell lines), and (iii) their cytotoxicity in a human lung cell line (A549). We identified five synthetic compounds with the potential to block SARS-CoV-2 infection, three of them without relevant toxicity in human lung cells. Xanthene 1 stood out as the most promising anti-SARS-CoV-2 agent, inhibiting viral infection and viral replication in Vero CCL-81 cells, without causing cytotoxicity to human lung cells.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- angiotensin converting enzyme
- induced apoptosis
- cell cycle arrest
- angiotensin ii
- cell surface
- signaling pathway
- single cell
- endoplasmic reticulum stress
- poor prognosis
- coronavirus disease
- cell therapy
- high throughput
- liver injury
- mesenchymal stem cells
- liver fibrosis
- protein protein
- breast cancer cells
- cell proliferation
- drug induced
- structure activity relationship