Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern
Year: 2024
Type: article
Abstract: The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants, some of which are resistant to vaccines and drugs targeting viral elements. Targeting host dependency factors, e.g. cellular proteins required for viral replication, would help prevent the development of resistance. However, it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors. To this end, we compared three variants of concern and found that the host transcriptional response was conserved, differing only in kinetics and magnitude. Clustered regularly interspaced short palindromic repeats screening identified host genes required for each variant during infection. Most of the genes were shared by multiple variants. We validated our hits with small molecules and repurposed the US Food and Drug Administration-approved drugs. All the drugs were highly active against all the tested variants, including new variants that emerged during the study (Delta and Omicron). Mechanistically, we identified reactive oxygen species production as a key step in early viral replication. Antioxidants such as N-acetyl cysteine (NAC) were effective against all the variants in both human lung cells and a humanized mouse model. Our study supports the use of available antioxidant drugs, such as NAC, as a general and effective anti-COVID-19 approach.
DOI: 10.1093/jmcb/mjae004
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,000
Funders: Bill and Melinda Gates Foundation, Massachusetts General Hospital, Giovanni Armenise-Harvard Foundation, European Commission, Fondazione Telethon, Ministero della Salute, Ministero dell’Istruzione, dell’Università e della Ricerca, Università degli Studi di Padova, Regione Campania, Associazione Italiana per la Ricerca sul Cancro, Università di Bologna, Fondazione Italiana per la Ricerca sul Cancro, Istituto Oncologico Veneto, Rijksinstituut voor Volksgezondheid en Milieu, European Regional Development Fund, H2020 European Research Council
Awards: G1026680634, G115398954, G1464101492, G1485050455, G156594879, G1678571033, G1761951791, University of Padua - to use small molecules to target G-quadruplexes within HIV to induce a signal for DNA degradation., G1859629608, G1888088267, G1933792690, G1953887145, G2035622065, G2269655010, G2484832597, G2572248831, G3373789935, G3421306691, G3845506083, G3970340483, European Virus Archive GLOBAL, G434337789, Dissecting the regulatory logic of cell fate reprogramming through integrative and single cell genomics, University of Padua - to target G-quadruplexes within HIV to induce a signal for DNA degradation, G6122222817, G671430033, G7629764078, G76646173, G7687256180, G8505034887, G8963630625
OpenAlex ID: W4391463706