Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of Lycorine

Autores
Maidana, Silvina Soledad; Romera, Sonia Alejandra; Marandino, Ana; Tau, Rocio Lucia; Shammas, Juan Manuel; Panzera, Yanina; Perez, Ruben
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
SARS-CoV-2 persists worldwide, driving the demand for effective antivirals that inhibit replication and limit the emergence of resistant variants. Lycorine, a non-nucleoside inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase, exhibits antiviral activity without direct mutagenic effects. Here, we examine the occurrence of single-nucleotide variants (SNVs) and insertions/deletions (indels) in SARS-CoV-2 B.1.499 strain during serial passages in Vero cells, comparing lycorine-treated cultures (2.5 and 5 µg/mL) with untreated controls. Whole-genome sequencing was used to assess mutation patterns and frequencies. Lycorine-treated passages displayed greater variant diversity than controls, with fixed mutations mainly affecting non-structural proteins (Nsp3-F1375A, Nsp5-L50F, and Nsp14-G265D) and the envelope protein (E-S6L). A 15-nucleotide deletion in the spike gene (QTQTN motif) occurred in both groups but became fixed only in untreated passages, suggesting negative selection under lycorine pressure. Notably, the L50F mutation in Nsp5, previously linked to nirmatrelvir resistance, was found exclusively in lycorine-treated passages. Additionally, a 1-nucleotide deletion in the accessory gene ORF8, detected only under lycorine treatment, resulted in a frameshift mutation that added four amino acids, potentially altering the protein’s function. Overall, lycorine induces a distinct mutation profile, favoring replication-related variants while suppressing deleterious deletions. These findings suggest potential mechanisms of cross-resistance and highlight the importance of monitoring resistance during clinical use.
Instituto de Virología
Fil: Maidana, Silvina Soledad. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; Argentina
Fil: Maidana, Silvina Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Maidana, Silvina Soledad. Universidad del Salvador. Facultad de Ciencias Agrarias y Veterinarias. Instituto de Investigación Veterinaria; Argentina
Fil: Romera, Sonia Alejandra. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; Argentina
Fil: Romera, Sonia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Romera, Sonia Alejandra. Universidad del Salvador. Facultad de Ciencias Agrarias y Veterinarias. Instituto de Investigación Veterinaria; Argentina
Fil: Marandino, Ana. Universidad de la República. Facultad de Ciencias. Instituto de Biología. Sección Genética Evolutiva; Uruguay
Fil: Tau, Rocio Lucia. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; Argentina
Fil: Tau, Rocio Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Shammas, Juan Manuel. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; Argentina
Fil: Shammas, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Panzera, Yanina. Universidad de la República. Facultad de Ciencias. Instituto de Biología. Sección Genética Evolutiva; Uruguay
Fil: Pérez, Ruben. Universidad de la República. Facultad de Ciencias. Instituto de Biología. Sección Genética Evolutiva; Uruguay
Fuente
COVID 5 (11) : 181. (October 2025)
Materia
Coronavirus del Síndrome Respiratorio Agudo Grave 2
Mutación
Agentes Antivirales
Severe Acute Respiratory Syndrome Coronavirus 2
Mutation
Antiviral Agents
SARS-CoV-2
Lycorine
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by-nc-sa/4.0/
Repositorio
INTA Digital (INTA)
Institución
Instituto Nacional de Tecnología Agropecuaria
OAI Identificador
oai:localhost:20.500.12123/24774
Acceder
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oai_identifier_str oai:localhost:20.500.12123/24774
network_acronym_str INTADig
repository_id_str l
network_name_str INTA Digital (INTA)
spelling Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of LycorineMaidana, Silvina SoledadRomera, Sonia AlejandraMarandino, AnaTau, Rocio LuciaShammas, Juan ManuelPanzera, YaninaPerez, RubenCoronavirus del Síndrome Respiratorio Agudo Grave 2MutaciónAgentes AntiviralesSevere Acute Respiratory Syndrome Coronavirus 2MutationAntiviral AgentsSARS-CoV-2LycorineSARS-CoV-2 persists worldwide, driving the demand for effective antivirals that inhibit replication and limit the emergence of resistant variants. Lycorine, a non-nucleoside inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase, exhibits antiviral activity without direct mutagenic effects. Here, we examine the occurrence of single-nucleotide variants (SNVs) and insertions/deletions (indels) in SARS-CoV-2 B.1.499 strain during serial passages in Vero cells, comparing lycorine-treated cultures (2.5 and 5 µg/mL) with untreated controls. Whole-genome sequencing was used to assess mutation patterns and frequencies. Lycorine-treated passages displayed greater variant diversity than controls, with fixed mutations mainly affecting non-structural proteins (Nsp3-F1375A, Nsp5-L50F, and Nsp14-G265D) and the envelope protein (E-S6L). A 15-nucleotide deletion in the spike gene (QTQTN motif) occurred in both groups but became fixed only in untreated passages, suggesting negative selection under lycorine pressure. Notably, the L50F mutation in Nsp5, previously linked to nirmatrelvir resistance, was found exclusively in lycorine-treated passages. Additionally, a 1-nucleotide deletion in the accessory gene ORF8, detected only under lycorine treatment, resulted in a frameshift mutation that added four amino acids, potentially altering the protein’s function. Overall, lycorine induces a distinct mutation profile, favoring replication-related variants while suppressing deleterious deletions. These findings suggest potential mechanisms of cross-resistance and highlight the importance of monitoring resistance during clinical use.Instituto de VirologíaFil: Maidana, Silvina Soledad. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; ArgentinaFil: Maidana, Silvina Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Maidana, Silvina Soledad. Universidad del Salvador. Facultad de Ciencias Agrarias y Veterinarias. Instituto de Investigación Veterinaria; ArgentinaFil: Romera, Sonia Alejandra. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; ArgentinaFil: Romera, Sonia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Romera, Sonia Alejandra. Universidad del Salvador. Facultad de Ciencias Agrarias y Veterinarias. Instituto de Investigación Veterinaria; ArgentinaFil: Marandino, Ana. Universidad de la República. Facultad de Ciencias. Instituto de Biología. Sección Genética Evolutiva; UruguayFil: Tau, Rocio Lucia. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; ArgentinaFil: Tau, Rocio Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Shammas, Juan Manuel. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; ArgentinaFil: Shammas, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Panzera, Yanina. Universidad de la República. Facultad de Ciencias. Instituto de Biología. Sección Genética Evolutiva; UruguayFil: Pérez, Ruben. Universidad de la República. Facultad de Ciencias. Instituto de Biología. Sección Genética Evolutiva; UruguayMDPI2025-12-26T14:54:52Z2025-12-26T14:54:52Z2025-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://hdl.handle.net/20.500.12123/24774https://www.mdpi.com/2673-8112/5/11/1812673-8112https://doi.org/10.3390/covid5110181COVID 5 (11) : 181. (October 2025)reponame:INTA Digital (INTA)instname:Instituto Nacional de Tecnología Agropecuariaenginfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-sa/4.0/Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)2026-04-01T11:49:52Zoai:localhost:20.500.12123/24774instacron:INTAInstitucionalhttp://repositorio.inta.gob.ar/Organismo científico-tecnológicoNo correspondehttp://repositorio.inta.gob.ar/oai/requesttripaldi.nicolas@inta.gob.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:l2026-04-01 11:49:52.917INTA Digital (INTA) - Instituto Nacional de Tecnología Agropecuariafalse
dc.title.none.fl_str_mv Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of Lycorine
title Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of Lycorine
spellingShingle Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of Lycorine
Maidana, Silvina Soledad
Coronavirus del Síndrome Respiratorio Agudo Grave 2
Mutación
Agentes Antivirales
Severe Acute Respiratory Syndrome Coronavirus 2
Mutation
Antiviral Agents
SARS-CoV-2
Lycorine
title_short Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of Lycorine
title_full Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of Lycorine
title_fullStr Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of Lycorine
title_full_unstemmed Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of Lycorine
title_sort Characterization of the SARS-CoV-2 Mutation Pattern Generated In Vitro by the Antiviral Action of Lycorine
dc.creator.none.fl_str_mv Maidana, Silvina Soledad
Romera, Sonia Alejandra
Marandino, Ana
Tau, Rocio Lucia
Shammas, Juan Manuel
Panzera, Yanina
Perez, Ruben
author Maidana, Silvina Soledad
author_facet Maidana, Silvina Soledad
Romera, Sonia Alejandra
Marandino, Ana
Tau, Rocio Lucia
Shammas, Juan Manuel
Panzera, Yanina
Perez, Ruben
author_role author
author2 Romera, Sonia Alejandra
Marandino, Ana
Tau, Rocio Lucia
Shammas, Juan Manuel
Panzera, Yanina
Perez, Ruben
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Coronavirus del Síndrome Respiratorio Agudo Grave 2
Mutación
Agentes Antivirales
Severe Acute Respiratory Syndrome Coronavirus 2
Mutation
Antiviral Agents
SARS-CoV-2
Lycorine
topic Coronavirus del Síndrome Respiratorio Agudo Grave 2
Mutación
Agentes Antivirales
Severe Acute Respiratory Syndrome Coronavirus 2
Mutation
Antiviral Agents
SARS-CoV-2
Lycorine
dc.description.none.fl_txt_mv SARS-CoV-2 persists worldwide, driving the demand for effective antivirals that inhibit replication and limit the emergence of resistant variants. Lycorine, a non-nucleoside inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase, exhibits antiviral activity without direct mutagenic effects. Here, we examine the occurrence of single-nucleotide variants (SNVs) and insertions/deletions (indels) in SARS-CoV-2 B.1.499 strain during serial passages in Vero cells, comparing lycorine-treated cultures (2.5 and 5 µg/mL) with untreated controls. Whole-genome sequencing was used to assess mutation patterns and frequencies. Lycorine-treated passages displayed greater variant diversity than controls, with fixed mutations mainly affecting non-structural proteins (Nsp3-F1375A, Nsp5-L50F, and Nsp14-G265D) and the envelope protein (E-S6L). A 15-nucleotide deletion in the spike gene (QTQTN motif) occurred in both groups but became fixed only in untreated passages, suggesting negative selection under lycorine pressure. Notably, the L50F mutation in Nsp5, previously linked to nirmatrelvir resistance, was found exclusively in lycorine-treated passages. Additionally, a 1-nucleotide deletion in the accessory gene ORF8, detected only under lycorine treatment, resulted in a frameshift mutation that added four amino acids, potentially altering the protein’s function. Overall, lycorine induces a distinct mutation profile, favoring replication-related variants while suppressing deleterious deletions. These findings suggest potential mechanisms of cross-resistance and highlight the importance of monitoring resistance during clinical use.
Instituto de Virología
Fil: Maidana, Silvina Soledad. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; Argentina
Fil: Maidana, Silvina Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Maidana, Silvina Soledad. Universidad del Salvador. Facultad de Ciencias Agrarias y Veterinarias. Instituto de Investigación Veterinaria; Argentina
Fil: Romera, Sonia Alejandra. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; Argentina
Fil: Romera, Sonia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Romera, Sonia Alejandra. Universidad del Salvador. Facultad de Ciencias Agrarias y Veterinarias. Instituto de Investigación Veterinaria; Argentina
Fil: Marandino, Ana. Universidad de la República. Facultad de Ciencias. Instituto de Biología. Sección Genética Evolutiva; Uruguay
Fil: Tau, Rocio Lucia. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; Argentina
Fil: Tau, Rocio Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Shammas, Juan Manuel. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología e Innovaciones Tecnológicas; Argentina
Fil: Shammas, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Panzera, Yanina. Universidad de la República. Facultad de Ciencias. Instituto de Biología. Sección Genética Evolutiva; Uruguay
Fil: Pérez, Ruben. Universidad de la República. Facultad de Ciencias. Instituto de Biología. Sección Genética Evolutiva; Uruguay
description SARS-CoV-2 persists worldwide, driving the demand for effective antivirals that inhibit replication and limit the emergence of resistant variants. Lycorine, a non-nucleoside inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase, exhibits antiviral activity without direct mutagenic effects. Here, we examine the occurrence of single-nucleotide variants (SNVs) and insertions/deletions (indels) in SARS-CoV-2 B.1.499 strain during serial passages in Vero cells, comparing lycorine-treated cultures (2.5 and 5 µg/mL) with untreated controls. Whole-genome sequencing was used to assess mutation patterns and frequencies. Lycorine-treated passages displayed greater variant diversity than controls, with fixed mutations mainly affecting non-structural proteins (Nsp3-F1375A, Nsp5-L50F, and Nsp14-G265D) and the envelope protein (E-S6L). A 15-nucleotide deletion in the spike gene (QTQTN motif) occurred in both groups but became fixed only in untreated passages, suggesting negative selection under lycorine pressure. Notably, the L50F mutation in Nsp5, previously linked to nirmatrelvir resistance, was found exclusively in lycorine-treated passages. Additionally, a 1-nucleotide deletion in the accessory gene ORF8, detected only under lycorine treatment, resulted in a frameshift mutation that added four amino acids, potentially altering the protein’s function. Overall, lycorine induces a distinct mutation profile, favoring replication-related variants while suppressing deleterious deletions. These findings suggest potential mechanisms of cross-resistance and highlight the importance of monitoring resistance during clinical use.
publishDate 2025
dc.date.none.fl_str_mv 2025-12-26T14:54:52Z
2025-12-26T14:54:52Z
2025-10
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12123/24774
https://www.mdpi.com/2673-8112/5/11/181
2673-8112
https://doi.org/10.3390/covid5110181
url http://hdl.handle.net/20.500.12123/24774
https://www.mdpi.com/2673-8112/5/11/181
https://doi.org/10.3390/covid5110181
identifier_str_mv 2673-8112
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv COVID 5 (11) : 181. (October 2025)
reponame:INTA Digital (INTA)
instname:Instituto Nacional de Tecnología Agropecuaria
reponame_str INTA Digital (INTA)
collection INTA Digital (INTA)
instname_str Instituto Nacional de Tecnología Agropecuaria
repository.name.fl_str_mv INTA Digital (INTA) - Instituto Nacional de Tecnología Agropecuaria
repository.mail.fl_str_mv tripaldi.nicolas@inta.gob.ar
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