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Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation.
Souza, Thiago Moreno L; Pinho, Vagner D; Setim, Cristina F; Sacramento, Carolina Q; Marcon, Rodrigo; Fintelman-Rodrigues, Natalia; Chaves, Otavio A; Heller, Melina; Temerozo, Jairo R; Ferreira, André C; Mattos, Mayara; Momo, Patrícia B; Dias, Suelen S G; Gesto, João S M; Pereira-Dutra, Filipe; Viola, João P B; Queiroz-Junior, Celso Martins; Guimarães, Lays Cordeiro; Chaves, Ian Meira; Guimarães, Pedro Pires Goulart; Costa, Vivian Vasconcelos; Teixeira, Mauro Martins; Bou-Habib, Dumith Chequer; Bozza, Patrícia T; Aguillón, Anderson R; Siqueira-Junior, Jarbas; Macedo-Junior, Sergio; Andrade, Edineia L; Fadanni, Guilherme P; Tolouei, Sara E L; Potrich, Francine B; Santos, Adara A; Marques, Naiani F; Calixto, João B; Rabi, Jaime A.
  • Souza TML; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil. thiago.moreno@fiocruz.br.
  • Pinho VD; 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.
  • Setim CF; Microbiológica Química e Farmacêutica, Doutor Nicanor, 238 Inhaúma, Rio de Janeiro, RJ, Brazil.
  • Sacramento CQ; 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.
  • Marcon R; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • Fintelman-Rodrigues N; 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; 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.
  • Heller M; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • Temerozo JR; 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.
  • Ferreira AC; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • Mattos M; 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; 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.
  • Dias SSG; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • Gesto JSM; National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil.
  • Pereira-Dutra F; Laboratório de Pesquisa sobre o Timo, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil.
  • Viola JPB; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • Queiroz-Junior CM; 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.
  • Guimarães LC; Universidade Iguaçu, Nova Iguaçu, RJ, Brazil.
  • Chaves IM; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • Guimarães PPG; 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.
  • Costa VV; Microbiológica Química e Farmacêutica, Doutor Nicanor, 238 Inhaúma, Rio de Janeiro, RJ, Brazil.
  • Teixeira MM; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • Bou-Habib DC; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • Bozza PT; 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.
  • Aguillón AR; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
  • Siqueira-Junior J; Program of Immunology and Tumor Biology, Brazilian National Cancer Institute (INCA), Rua André Cavalcanti 37, 5th floor, Centro, Rio de Janeiro, Brazil.
  • Macedo-Junior S; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil.
  • Andrade EL; Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
  • Fadanni GP; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil.
  • Tolouei SEL; Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
  • Potrich FB; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil.
  • Santos AA; Centro de Pesquisa e Desenvolvimento de Fármacos, Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil.
  • Marques NF; National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil.
  • Calixto JB; Laboratório de Pesquisa sobre o Timo, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil.
  • Rabi JA; Laboratório de Imunofarmacologia, Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
Nat Commun ; 14(1): 199, 2023 01 13.
Article in English | MEDLINE | ID: covidwho-2185848
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2023 Document Type: Article Affiliation country: S41467-023-35928-z

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2023 Document Type: Article Affiliation country: S41467-023-35928-z