20.500.12556/DiRROS-30004 In silico characterisation of a novel SARS-CoV-2 envelope protein inhibitor and in vitro validation against murine coronavirus 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. SARS-CoV-2 envelope protein viroporin ion channel blockers molecular docking molecular dynamics simulations drug discovery murine hepatitis virus in vitro protein ovojnice SARS-CoV-2 viroporin zaviralci ionskih kanalov molekulsko sidranje simulacije molekulske dinamike odkrivanje učinkovin virus mišjega hepatitisa in vitro true false false Angleški jezik Slovenski jezik Neznano 2026-06-11 12:23:19 2026-06-11 12:23:19 2026-06-12 03:54:43 0000-00-00 00:00:00 2026 0 0 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; str. 1-14 [article no.] 109949 Vol. 178 2026 0000-00-00 Zaloznikova NiDoloceno NiDoloceno 0000-00-00 0000-00-00 2026-08-15 578 1090-2120 10.1016/j.bioorg.2026.109949 278547459 https://www.sciencedirect.com/science/article/pii/S0045206826004852 1 92bfc186-657f-11f1-9215-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=45212 RAZ_Kobe_Nina_2026.pdf RAZ_Kobe_Nina_2026.pdf 1 02107C0D09FFA5A88A736A06510C370E e21dda57e671fd8928d90b26656fc2ac6d7b1388781f39fd34a533520869ef7b 1d03f0f6-6580-11f1-9215-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=45213 Nacionalni inštitut za biologijo 0 0 0