Author:
Abatematteo Francesca Serena,Delre Pietro,Mercurio Ivan,Rezelj Veronica V.,Siliqi Dritan,Beaucourt Stephanie,Lattanzi Gianluca,Colabufo Nicola Antonio,Leopoldo Marcello,Saviano Michele,Vignuzzi Marco,Mangiatordi Giuseppe Felice,Abate Carmen
Abstract
AbstractThe development of effective drugs to treat coronavirus infections remains a significant challenge for the scientific community. Recent evidence reports on the sigma-1 receptor (S1R) as a key druggable host protein in the SARS-CoV-1 and SARS-CoV-2 interactomes and shows a potent antiviral activity against SARS-CoV-2 for the S1R antagonist PB28. To improve PB28 activity, we designed and tested a series of its analogues and identified a compound that is fourfold more potent against SARS-CoV-2 than PB28 itself. Interestingly, we found no direct correlation between S1R affinity and SARS-CoV-2 antiviral activity. Building on this, we employed comparative induced fit docking and molecular dynamics simulations to gain insights into the possible mechanism that occurs when specific ligand–protein interactions take place and that may be responsible for the observed antiviral activity. Our findings offer a possible explanation for the experimental observations, provide insights into the S1R conformational changes upon ligand binding and lay the foundation for the rational design of new S1R ligands with potent antiviral activity against SARS-CoV-2 and likely other viruses.
Funder
Consiglio Nazionale delle Ricerche
Publisher
Springer Science and Business Media LLC
Reference54 articles.
1. SARS | Basics Factsheet | CDC. https://www.cdc.gov/sars/about/fs-sars.html.
2. Memish, Z. A., Perlman, S., Van Kerkhove, M. D. & Zumla, A. Middle East respiratory syndrome. Lancet 395, 1063–1077 (2020).
3. Coronavirus Disease (COVID-19) Situation Reports. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports.
4. Delre, P., Caporuscio, F., Saviano, M. & Mangiatordi, G. F. Repurposing known drugs as covalent and non-covalent inhibitors of the SARS-CoV-2 papain-like protease. Front. Chem. https://doi.org/10.3389/fchem.2020.594009 (2020).
5. Ali, F. et al. Implication of in silico studies in the search for novel inhibitors against SARS-CoV-2. Arch. Pharm. (Weinheim) 355, e2100360 (2022).
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献