A conformational rearrangement of the SARS-CoV-2 host protein sigma-1 is required for antiviral activity: insights from a combined in-silico/in-vitro approach
Francesca Serena Abatematteo, Pietro Delre, Ivan Mercurio, Veronica V Rezelj, Dritan Siliqi, Stephanie Beaucourt, Gianluca Lattanzi, Nicola Antonio Colabufo, Marcello Leopoldo, Michele Saviano, Marco Vignuzzi, Giuseppe Felice Mangiatordi, Carmen Abate
Scientific Reports, doi:10.1038/s41598-023-39662-w
The 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 ligandprotein 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.
Abbreviations (S1R) Sigma-1 receptor (CNS) Central nervous system (SARS) Severe acute respiratory syndrome (MERS) Middle East respiratory syndrome (COVID-19) Coronavirus disease 2019 (FDA) Food and Drug Administration (S2R) Sigma-2 receptor (KO) Knocking out (KD) Knocking down (IFD) Induced Fit Docking
Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by C.A. and G.F.M. Computational studies and analyses were performed by P.D., I.M., G.L. and G.F.M. Anti-SARS-CoV-2 assays were designed and performed by V.R., S.B. and M.V. Synthesis of S1R ligands was performed by F.S.A. The first draft of the manuscript was written by C.A. and G.F.M. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Competing interests The authors declare no competing interests.
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