دورية أكاديمية
أعرض في EDS

Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation.

التفاصيل البيبلوغرافية
العنوان: Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation.
المؤلفون: Souza TML; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil. thiago.moreno@fiocruz.br.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil. thiago.moreno@fiocruz.br., Pinho VD; Microbiológica Química e Farmacêutica, Doutor Nicanor, 238 Inhaúma, Rio de Janeiro, RJ, Brazil., Setim CF; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Sacramento CQ; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Marcon R; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Fintelman-Rodrigues N; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Chaves OA; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Heller M; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Temerozo JR; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil.; Laboratório de Pesquisa sobre o Timo, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil., Ferreira AC; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil.; Universidade Iguaçu, Nova Iguaçu, RJ, Brazil., Mattos M; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Momo PB; Microbiológica Química e Farmacêutica, Doutor Nicanor, 238 Inhaúma, Rio de Janeiro, RJ, Brazil., Dias SSG; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil., Gesto JSM; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.; National Institute for Science and Technology on Innovation in Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil., Pereira-Dutra F; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil., Viola JPB; Program of Immunology and Tumor Biology, Brazilian National Cancer Institute (INCA), Rua André Cavalcanti 37, 5th floor, Centro, Rio de Janeiro, Brazil., Queiroz-Junior CM; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil., Guimarães LC; Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil., Chaves IM; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil., Guimarães PPG; Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil., Costa VV; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil., Teixeira MM; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil., Bou-Habib DC; National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil.; Laboratório de Pesquisa sobre o Timo, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil., Bozza PT; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil., Aguillón AR; Microbiológica Química e Farmacêutica, Doutor Nicanor, 238 Inhaúma, Rio de Janeiro, RJ, Brazil., Siqueira-Junior J; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Macedo-Junior S; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Andrade EL; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Fadanni GP; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Tolouei SEL; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Potrich FB; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Santos AA; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Marques NF; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil., Calixto JB; Centro de Inovação e Ensaios Pré-clínicos and National Institute for Science and Technology on Innovation in Medicines and Identification of New Therapeutics Targets (INCT-INOVAMED). Avenida Luiz Boiteux Piazza, 1302 Cachoeira do Bom Jesus, 88056-000, Florianópolis, SC, Brazil. joao.calixto@cienp.org.br., Rabi JA; Microbiológica Química e Farmacêutica, Doutor Nicanor, 238 Inhaúma, Rio de Janeiro, RJ, Brazil. jrabi@microbiologica.ind.br.
المصدر: Nature communications [Nat Commun] 2023 Jan 13; Vol. 14 (1), pp. 199. Date of Electronic Publication: 2023 Jan 13.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Antiviral Agents*/pharmacology , Antiviral Agents*/therapeutic use , COVID-19*, Animals ; Humans ; Mice ; SARS-CoV-2 ; Kinetin/pharmacology ; Inflammation/drug therapy ; Nucleotides ; Virus Replication
مستخلص: Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce error-prone virus replication. Coinhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously incorporated nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. MB-905 shows good oral absorption, its metabolites are stable, achieving long-lasting plasma and lung concentrations, and this drug is not mutagenic nor cardiotoxic in acute and chronic treatments. SARS-CoV-2-infected hACE-mice and hamsters treated with MB-905 show decreased viral replication, lung necrosis, hemorrhage and inflammation. Because kinetin is clinically investigated for a rare genetic disease at regimens beyond the predicted concentrations of antiviral/anti-inflammatory inhibition, our investigation suggests the opportunity for the rapid clinical development of a new antiviral substance for the treatment of COVID-19.
(© 2023. The Author(s).)
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المشرفين على المادة: 0 (Antiviral Agents)
P39Y9652YJ (Kinetin)
0 (Nucleotides)
تواريخ الأحداث: Date Created: 20230113 Date Completed: 20230117 Latest Revision: 20230307
رمز التحديث: 20230308
مُعرف محوري في PubMed: PMC9837764
DOI: 10.1038/s41467-023-35928-z
PMID: 36639383
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-023-35928-z