| Title: | In silico characterisation of a novel SARS-CoV-2 envelope protein inhibitor and in vitro validation against murine coronavirus |
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| Authors: | ID Kobe, Nina (Author)
ID Dreisewerd, Lennart (Author)
ID Lukšič, Miha (Author)
ID Pavlin, Matic (Author)
ID Grošelj, Uroš (Author)
ID Podlipnik, Črtomir (Author)
ID Janc, Mojca (Author)
ID Lengar, Živa (Author)
ID Mrak, Polona (Author)
ID Tušek-Žnidarič, Magda (Author)
ID Pompe Novak, Maruša (Author)
ID Kuhar, Urška (Author)
ID Hostnik, Peter (Author)
ID Dattola, Federica (Author)
ID Carletti, Tea (Author)
ID Marcello, Alessandro (Author)
ID Kogovšek, Polona (Author) |
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| Files: |  URL - Source URL, visit https://www.sciencedirect.com/science/article/pii/S0045206826004852
 PDF - Presentation file, download (9,89 MB)
MD5: 02107C0D09FFA5A88A736A06510C370E
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| Language: | English |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: |  NIB - National Institute of Biology
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| Abstract: | The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses a challenge to current therapies and emphasises the need for targets that are less susceptible to mutation. The SARS-CoV-2 envelope protein (Epro) is a highly conserved viroporin and is of central importance to the viral life cycle, yet it remains underexplored as a therapeutic target. In this study, we have identified and characterised a novel lead candidate (LC) − (S)-N-(2-((1S,3S,5S,7S)-adamantan-2-yl)ethyl)-2-(butylamino)-3-(1H-indol-3-yl)propanamide − for inhibition of the SARS-CoV-2 Epro ion channel using combined in silico and in vitro approaches. Molecular dynamics (MD) simulations showed that LC forms stable complexes at the N-terminal vestibule, with key interactions at GLU8, THR9, THR11, ASN15, and LEU18, and a calculated binding affinity higher than that of the reference compound rimantadine within the applied MD/molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) framework. Results of in vitro experiments indicated that LC inhibits the model coronavirus murine hepatitis virus at late stages of the viral cycle. Activity under co-treatment conditions further suggests a direct virucidal effect or interference with early entry stages; an EC50 of approximately 12 μM was within the same micromolar range as those observed for the reference Epro inhibitors 5-(N,N-hexamethylene)amiloride and rimantadine. Quantitative PCR experiments showed delayed RNA replication in LC-treated infected cells, while light and transmission electron microscopy displayed the reduced release of virions and prevention of cell lysis. These results emphasise the central role of the Epro ion channel in the coronavirus life cycle and present LC as a promising candidate for the further development of novel coronavirus inhibitors. |
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| Keywords: | SARS-CoV-2 envelope protein, viroporin, ion channel blockers, molecular docking, molecular dynamics simulations, drug discovery, murine hepatitis virus, in vitro |
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| Publication version: | Version of Record |
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| Publication date: | 15.08.2026 |
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| Year of publishing: | 2026 |
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| Number of pages: | str. 1-14 |
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| Numbering: | Vol. 178, [article no.] 109949 |
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| PID: | 20.500.12556/DiRROS-30004  |
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| UDC: | 578 |
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| ISSN on article: | 1090-2120 |
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| DOI: | 10.1016/j.bioorg.2026.109949 |
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| COBISS.SI-ID: | 278547459 |
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| Note: | Nasl. z nasl. zaslona;
Soavtorji: Lennart Dreisewerd, Miha Lukšič, Matic Pavlin, Uroš Grošelj, Črtomir Podlipnik, Mojca Janc, Živa Lengar, Polona Mrak, Magda Tušek Žnidarič, Maruša Pompe Novak, Urška Kuhar, Peter Hostnik, Federica Dattola, Tea Carletti, Alessandro Marcello, Polona Kogovšek;
Opis vira z dne 18. 5. 2026;
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| Publication date in DiRROS: | 11.06.2026 |
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| Views: | 110 |
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| Downloads: | 84 |
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