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

Thiago Moreno L. Souza (), Vagner D. Pinho, Cristina F. Setim, Carolina Q. Sacramento, Rodrigo Marcon, Natalia Fintelman-Rodrigues, Otavio A. Chaves, Melina Heller, Jairo R. Temerozo, André C. Ferreira, Mayara Mattos, Patrícia B. Momo, Suelen S. G. Dias, João S. M. Gesto, Filipe Pereira-Dutra, João P. B. Viola, Celso Martins Queiroz-Junior, Lays Cordeiro Guimarães, Ian Meira Chaves, Pedro Pires Goulart Guimarães, Vivian Vasconcelos Costa, Mauro Martins Teixeira, Dumith Chequer Bou-Habib, Patrícia T. Bozza, Anderson R. Aguillón, Jarbas Siqueira-Junior, Sergio Macedo-Junior, Edineia L. Andrade, Guilherme P. Fadanni, Sara E. L. Tolouei, Francine B. Potrich, Adara A. Santos, Naiani F. Marques, João B. Calixto () and Jaime A. Rabi ()
Additional contact information
Thiago Moreno L. Souza: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
Vagner D. Pinho: Doutor Nicanor
Cristina F. Setim: 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
Carolina Q. Sacramento: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
Rodrigo Marcon: 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
Natalia Fintelman-Rodrigues: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
Otavio A. Chaves: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
Melina Heller: 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
Jairo R. Temerozo: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
André C. Ferreira: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
Mayara Mattos: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
Patrícia B. Momo: Doutor Nicanor
Suelen S. G. Dias: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
João S. M. Gesto: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
Filipe Pereira-Dutra: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
João P. B. Viola: Brazilian National Cancer Institute (INCA), Rua André Cavalcanti 37
Celso Martins Queiroz-Junior: Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG)
Lays Cordeiro Guimarães: Institute of Biological Sciences, Universidade Federal de Minas Gerais
Ian Meira Chaves: Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG)
Pedro Pires Goulart Guimarães: Institute of Biological Sciences, Universidade Federal de Minas Gerais
Vivian Vasconcelos Costa: Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG)
Mauro Martins Teixeira: Instituto de Ciências Biológicas, (ICB), Universidade Federal de Minas Gerais (UFMG)
Dumith Chequer Bou-Habib: Oswaldo Cruz Institute, Fiocruz
Patrícia T. Bozza: Oswaldo Cruz Institute, Fundação Oswaldo Cruz (Fiocruz)
Anderson R. Aguillón: Doutor Nicanor
Jarbas Siqueira-Junior: 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
Sergio Macedo-Junior: 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
Edineia L. Andrade: 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
Guilherme P. Fadanni: 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
Sara E. L. Tolouei: 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
Francine B. Potrich: 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
Adara A. Santos: 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
Naiani F. Marques: 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
João B. Calixto: 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
Jaime A. Rabi: Doutor Nicanor

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-35928-z

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