biostudies-literatureBekdash RIrving Medical Center, Columbia Universitye3002522https://www.ebi.ac.uk/biostudies/studies/S-EPMC10939250biostudies-literatureUnknown22(3)Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected approximately 800 million people since the start of the Coronavirus Disease 2019 (COVID-19) pandemic. Because of the high rate of mutagenesis in SARS-CoV-2, it is difficult to develop a sustainable approach for prevention and treatment. The Envelope (E) protein is highly conserved among human coronaviruses. Previous studies reported that SARS-CoV-1 E deficiency reduced viral propagation, suggesting that E inhibition might be an effective therapeutic strategy for SARS-CoV-2. Here, we report inhibitory peptides against SARS-CoV-2 E protein named iPep-SARS2-E. Leveraging E-induced alterations in proton homeostasis and NFAT/AP-1 pathway in mammalian cells, we developed screening platforms to design and optimize the peptiPLoS biologyDeveloping inhibitory peptides against SARS-CoV-2 envelope protein.PMC10939250TRx award programDean’s Office FundHo DDNair MSHuang YYazawa MTsai HYAhdout JBekdash RYoshida KQiu LUryu KSoni RKfalseDeveloping inhibitory peptides against SARS-CoV-2 envelope protein.Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected approximately 800 million people since the start of the Coronavirus Disease 2019 (COVID-19) pandemic. Because of the high rate of mutagenesis in SARS-CoV-2, it is difficult to develop a sustainable approach for prevention and treatment. The Envelope (E) protein is highly conserved among human coronaviruses. Previous studies reported that SARS-CoV-1 E deficiency reduced viral propagation, suggesting that E inhibition might be an effective therapeutic strategy for SARS-CoV-2. Here, we report inhibitory peptides against SARS-CoV-2 E protein named iPep-SARS2-E. Leveraging E-induced alterations in proton homeostasis and NFAT/AP-1 pathway in mammalian cells, we developed screening platforms to design and optimize the pepti2024-01-01T00:00:00Z2024 Mar2026-07-15T07:38:10.609Z2026-07-01T03:07:38.639ZS-EPMC109392503848388710.1371/journal.pbio.3002522