Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection

Autores
Smith, Jason R.; Toro, Ayelen Rayen; Sabater, Agustina Ayelen; Kovacic, Suzana; Ban, Fuqiang; Arevalo, Ana P.; Crispo, Martina; Gueron, Geraldine; Young, Robert N.; Cherkasov, Artem
Año de publicación
2026
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Herein we report the development of novel covalent inhibitors of the SARS-CoV-2 main protease (Mpro). The developed compounds VPC285785 and VPC285786 demonstrated moderate inhibition of Mpro (IC50 0.8 µM vs. Nirmatrelvir 0.03 µM), whereas VPC285786 additionally inhibited human cathepsin L (CatL; IC50 4.2 µM vs Nirmatrelvir > 100 µM). In vitro metabolic stability studies in human and mouse microsomes revealed that VPC285786 demonstrated enhanced metabolic stability compared to Nirmatrelvir, with minimal turnover observed during the experimental window. Subsequent mass spectrometry analysis identified putative metabolic products consistent with previously reported oxidation patterns. Pharmacokinetic studies in mice demonstrated that VPC285785 achieved 15% oral bioavailability, supporting the potential for oral administration, whereas VPC285786 showed limited oral exposure despite superior metabolic stability. A side-by-side efficacy study of VPC285785 and Nirmatrelvir in a Murine Hepatitis Virus (MHV) infection model demonstrated that VPC285785 significantly reduced viral load in liver, brain, and spleen tissues compared to vehicle- and Nirmatrelvir-treated controls, while maintaining healthy liver function parameters. These results lay the foundation for further development of VPC285785-series antivirals that could be used as oral, single-agent therapies for SARS-CoV-2 infection, particularly given their dual-targeting mechanism and favorable toxicity profile.
Fil: Smith, Jason R.. University of British Columbia; Canadá
Fil: Toro, Ayelen Rayen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Sabater, Agustina Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Kovacic, Suzana. Simon Fraser University; Canadá
Fil: Ban, Fuqiang. University of British Columbia; Canadá
Fil: Arevalo, Ana P.. Instituto Pasteur de Montevideo; Uruguay
Fil: Crispo, Martina. Instituto Pasteur de Montevideo; Uruguay
Fil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Young, Robert N.. Simon Fraser University; Canadá
Fil: Cherkasov, Artem. University of British Columbia; Canadá
Materia
COVID-19
SARS-CoV-2 main protease
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/290153
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/290153
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infectionSmith, Jason R.Toro, Ayelen RayenSabater, Agustina AyelenKovacic, SuzanaBan, FuqiangArevalo, Ana P.Crispo, MartinaGueron, GeraldineYoung, Robert N.Cherkasov, ArtemCOVID-19SARS-CoV-2 main proteasehttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Herein we report the development of novel covalent inhibitors of the SARS-CoV-2 main protease (Mpro). The developed compounds VPC285785 and VPC285786 demonstrated moderate inhibition of Mpro (IC50 0.8 µM vs. Nirmatrelvir 0.03 µM), whereas VPC285786 additionally inhibited human cathepsin L (CatL; IC50 4.2 µM vs Nirmatrelvir > 100 µM). In vitro metabolic stability studies in human and mouse microsomes revealed that VPC285786 demonstrated enhanced metabolic stability compared to Nirmatrelvir, with minimal turnover observed during the experimental window. Subsequent mass spectrometry analysis identified putative metabolic products consistent with previously reported oxidation patterns. Pharmacokinetic studies in mice demonstrated that VPC285785 achieved 15% oral bioavailability, supporting the potential for oral administration, whereas VPC285786 showed limited oral exposure despite superior metabolic stability. A side-by-side efficacy study of VPC285785 and Nirmatrelvir in a Murine Hepatitis Virus (MHV) infection model demonstrated that VPC285785 significantly reduced viral load in liver, brain, and spleen tissues compared to vehicle- and Nirmatrelvir-treated controls, while maintaining healthy liver function parameters. These results lay the foundation for further development of VPC285785-series antivirals that could be used as oral, single-agent therapies for SARS-CoV-2 infection, particularly given their dual-targeting mechanism and favorable toxicity profile.Fil: Smith, Jason R.. University of British Columbia; CanadáFil: Toro, Ayelen Rayen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Sabater, Agustina Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Kovacic, Suzana. Simon Fraser University; CanadáFil: Ban, Fuqiang. University of British Columbia; CanadáFil: Arevalo, Ana P.. Instituto Pasteur de Montevideo; UruguayFil: Crispo, Martina. Instituto Pasteur de Montevideo; UruguayFil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Young, Robert N.. Simon Fraser University; CanadáFil: Cherkasov, Artem. University of British Columbia; CanadáNature2026-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/290153Smith, Jason R.; Toro, Ayelen Rayen; Sabater, Agustina Ayelen; Kovacic, Suzana; Ban, Fuqiang; et al.; Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection; Nature; Scientific Reports; 16; 1; 2-2026; 1-162045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-026-36842-2info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-026-36842-2info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T15:46:40Zoai:ri.conicet.gov.ar:11336/290153instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-08-25 15:46:41.046CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection
title Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection
spellingShingle Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection
Smith, Jason R.
COVID-19
SARS-CoV-2 main protease
title_short Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection
title_full Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection
title_fullStr Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection
title_full_unstemmed Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection
title_sort Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection
dc.creator.none.fl_str_mv Smith, Jason R.
Toro, Ayelen Rayen
Sabater, Agustina Ayelen
Kovacic, Suzana
Ban, Fuqiang
Arevalo, Ana P.
Crispo, Martina
Gueron, Geraldine
Young, Robert N.
Cherkasov, Artem
author Smith, Jason R.
author_facet Smith, Jason R.
Toro, Ayelen Rayen
Sabater, Agustina Ayelen
Kovacic, Suzana
Ban, Fuqiang
Arevalo, Ana P.
Crispo, Martina
Gueron, Geraldine
Young, Robert N.
Cherkasov, Artem
author_role author
author2 Toro, Ayelen Rayen
Sabater, Agustina Ayelen
Kovacic, Suzana
Ban, Fuqiang
Arevalo, Ana P.
Crispo, Martina
Gueron, Geraldine
Young, Robert N.
Cherkasov, Artem
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv COVID-19
SARS-CoV-2 main protease
topic COVID-19
SARS-CoV-2 main protease
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Herein we report the development of novel covalent inhibitors of the SARS-CoV-2 main protease (Mpro). The developed compounds VPC285785 and VPC285786 demonstrated moderate inhibition of Mpro (IC50 0.8 µM vs. Nirmatrelvir 0.03 µM), whereas VPC285786 additionally inhibited human cathepsin L (CatL; IC50 4.2 µM vs Nirmatrelvir > 100 µM). In vitro metabolic stability studies in human and mouse microsomes revealed that VPC285786 demonstrated enhanced metabolic stability compared to Nirmatrelvir, with minimal turnover observed during the experimental window. Subsequent mass spectrometry analysis identified putative metabolic products consistent with previously reported oxidation patterns. Pharmacokinetic studies in mice demonstrated that VPC285785 achieved 15% oral bioavailability, supporting the potential for oral administration, whereas VPC285786 showed limited oral exposure despite superior metabolic stability. A side-by-side efficacy study of VPC285785 and Nirmatrelvir in a Murine Hepatitis Virus (MHV) infection model demonstrated that VPC285785 significantly reduced viral load in liver, brain, and spleen tissues compared to vehicle- and Nirmatrelvir-treated controls, while maintaining healthy liver function parameters. These results lay the foundation for further development of VPC285785-series antivirals that could be used as oral, single-agent therapies for SARS-CoV-2 infection, particularly given their dual-targeting mechanism and favorable toxicity profile.
Fil: Smith, Jason R.. University of British Columbia; Canadá
Fil: Toro, Ayelen Rayen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Sabater, Agustina Ayelen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Kovacic, Suzana. Simon Fraser University; Canadá
Fil: Ban, Fuqiang. University of British Columbia; Canadá
Fil: Arevalo, Ana P.. Instituto Pasteur de Montevideo; Uruguay
Fil: Crispo, Martina. Instituto Pasteur de Montevideo; Uruguay
Fil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Young, Robert N.. Simon Fraser University; Canadá
Fil: Cherkasov, Artem. University of British Columbia; Canadá
description Herein we report the development of novel covalent inhibitors of the SARS-CoV-2 main protease (Mpro). The developed compounds VPC285785 and VPC285786 demonstrated moderate inhibition of Mpro (IC50 0.8 µM vs. Nirmatrelvir 0.03 µM), whereas VPC285786 additionally inhibited human cathepsin L (CatL; IC50 4.2 µM vs Nirmatrelvir > 100 µM). In vitro metabolic stability studies in human and mouse microsomes revealed that VPC285786 demonstrated enhanced metabolic stability compared to Nirmatrelvir, with minimal turnover observed during the experimental window. Subsequent mass spectrometry analysis identified putative metabolic products consistent with previously reported oxidation patterns. Pharmacokinetic studies in mice demonstrated that VPC285785 achieved 15% oral bioavailability, supporting the potential for oral administration, whereas VPC285786 showed limited oral exposure despite superior metabolic stability. A side-by-side efficacy study of VPC285785 and Nirmatrelvir in a Murine Hepatitis Virus (MHV) infection model demonstrated that VPC285785 significantly reduced viral load in liver, brain, and spleen tissues compared to vehicle- and Nirmatrelvir-treated controls, while maintaining healthy liver function parameters. These results lay the foundation for further development of VPC285785-series antivirals that could be used as oral, single-agent therapies for SARS-CoV-2 infection, particularly given their dual-targeting mechanism and favorable toxicity profile.
publishDate 2026
dc.date.none.fl_str_mv 2026-02
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/11336/290153
Smith, Jason R.; Toro, Ayelen Rayen; Sabater, Agustina Ayelen; Kovacic, Suzana; Ban, Fuqiang; et al.; Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection; Nature; Scientific Reports; 16; 1; 2-2026; 1-16
2045-2322
CONICET Digital
CONICET
url http://hdl.handle.net/11336/290153
identifier_str_mv Smith, Jason R.; Toro, Ayelen Rayen; Sabater, Agustina Ayelen; Kovacic, Suzana; Ban, Fuqiang; et al.; Pharmacokinetics, pathology and efficacy of SARS-CoV-2 main protease inhibitor VPC285785 in a murine model of coronavirus infection; Nature; Scientific Reports; 16; 1; 2-2026; 1-16
2045-2322
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-026-36842-2
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature
publisher.none.fl_str_mv Nature
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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