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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

Abatematteo et al., Scientific Reports, doi:10.1038/s41598-023-39662-w
Aug 2023  
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27th treatment shown to reduce risk in November 2021
 
*, now with p = 0.00014 from 21 studies, recognized in 3 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments. c19early.org
In Vitro and In Silico analysis supporting fluvoxamine for COVID-19. Authors investigated the mechanism of action of sigma-1 receptor (S1R) ligands for inhibiting SARS-CoV-2 replication, testing a series of S1R ligands and finding that some had potent antiviral activity against SARS-CoV-2 while others did not, even though they bound to S1R with similar affinity. Computational modeling suggested that specific ligand-protein interactions induce conformational changes in S1R that may be responsible for the antiviral effects. The findings provide insights into how S1R modulation could inhibit coronavirus replication and support further investigation of S1R-targeting drugs as potential COVID-19 treatments. However, a direct correlation between S1R affinity and antiviral potency was not found, indicating the mechanism may be more complex. Fluvoxamine is known to be a potent S1R agonist, with high binding affinity. This study found that some S1R ligands with nanomolar binding affinity had potent anti-SARS-CoV-2 effects in vitro. The computational modeling suggests the antiviral effects are due to conformational changes induced in S1R upon binding specific ligands. As a potent S1R agonist, fluvoxamine is likely to bind and induce conformational changes.
3 preclinical studies support the efficacy of fluvoxamine for COVID-19:
Abatematteo et al., 7 Aug 2023, peer-reviewed, 13 authors. Contact: giuseppe.mangiatordi@ic.cnr.it, carmen.abate@uniba.it.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperFluvoxamineAll
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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N-aryl- or N-alkylpiperazine derivatives: The role of ' 'N-substituent on σ1, σ2, 5-HT1A and D2 receptor affinity. Med. Chem. ' 'Res. 10, 201–207 (2000).', 'journal-title': 'Med. Chem. Res.'}, { 'key': '39662_CR44', 'doi-asserted-by': 'publisher', 'first-page': '1022', 'DOI': '10.1021/jm1013133', 'volume': '54', 'author': 'C Abate', 'year': '2011', 'unstructured': 'Abate, C. et al. Analogues of σ receptor ligand ' '1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine ' '(PB28) with added polar functionality and reduced lipophilicity for ' 'potential use as positron emission tomography radiotracers. J. Med. ' 'Chem. 54, 1022–1032 (2011).', 'journal-title': 'J. Med. Chem.'}, { 'key': '39662_CR45', 'doi-asserted-by': 'publisher', 'first-page': '2026', 'DOI': '10.1002/cmdc.201300291', 'volume': '8', 'author': 'M Niso', 'year': '2013', 'unstructured': 'Niso, M. et al. 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Nat Commun 13, ' '1267 (2022).', 'journal-title': 'Nat Commun'}, { 'key': '39662_CR52', 'doi-asserted-by': 'publisher', 'first-page': '1487', 'DOI': '10.3390/jpm12091487', 'volume': '12', 'author': 'AS Gouda', 'year': '2022', 'unstructured': 'Gouda, A. S. & Mégarbane, B. Molecular bases of serotonin reuptake ' 'inhibitor antidepressant-attributed effects in COVID-19: A new insight ' 'on the role of bradykinins. J. Personaliz. Med. 12, 1487 (2022).', 'journal-title': 'J. Personaliz. Med.'}, { 'key': '39662_CR53', 'first-page': '1461', 'volume': '18', 'author': 'S-YA Tsai', 'year': '2014', 'unstructured': 'Tsai, S.-Y.A., Pokrass, M. J., Klauer, N. R., De Credico, N. E. & Su, ' 'T.-P. Sigma-1 receptor chaperones in neurodegenerative and psychiatric ' 'disorders. 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