tetano
Editor, Senior Moderator
Nat Commun
. 2023 Jan 13;14(1):199.
doi: 10.1038/s41467-023-35928-z.
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation
Thiago Moreno L Souza[SUP] #[/SUP][SUP] 1 2 [/SUP], Vagner D Pinho[SUP] 3 [/SUP], Cristina F Setim[SUP] 4 [/SUP], Carolina Q Sacramento[SUP] 5 6 [/SUP], Rodrigo Marcon[SUP] 4 [/SUP], Natalia Fintelman-Rodrigues[SUP] 5 6 [/SUP], Otavio A Chaves[SUP] 5 6 [/SUP], Melina Heller[SUP] 4 [/SUP], Jairo R Temerozo[SUP] 5 7 8 [/SUP], André C Ferreira[SUP] 5 6 9 [/SUP], Mayara Mattos[SUP] 5 6 [/SUP], Patrícia B Momo[SUP] 3 [/SUP], Suelen S G Dias[SUP] 5 [/SUP], João S M Gesto[SUP] 5 6 [/SUP], Filipe Pereira-Dutra[SUP] 5 [/SUP], João P B Viola[SUP] 10 [/SUP], Celso Martins Queiroz-Junior[SUP] 11 [/SUP], Lays Cordeiro Guimarães[SUP] 12 [/SUP], Ian Meira Chaves[SUP] 11 [/SUP], Pedro Pires Goulart Guimarães[SUP] 12 [/SUP], Vivian Vasconcelos Costa[SUP] 11 [/SUP], Mauro Martins Teixeira[SUP] 11 [/SUP], Dumith Chequer Bou-Habib[SUP] 7 8 [/SUP], Patrícia T Bozza[SUP] 5 [/SUP], Anderson R Aguillón[SUP] 3 [/SUP], Jarbas Siqueira-Junior[SUP] 4 [/SUP], Sergio Macedo-Junior[SUP] 4 [/SUP], Edineia L Andrade[SUP] 4 [/SUP], Guilherme P Fadanni[SUP] 4 [/SUP], Sara E L Tolouei[SUP] 4 [/SUP], Francine B Potrich[SUP] 4 [/SUP], Adara A Santos[SUP] 4 [/SUP], Naiani F Marques[SUP] 4 [/SUP], João B Calixto[SUP] #[/SUP][SUP] 13 [/SUP], Jaime A Rabi[SUP] #[/SUP][SUP] 14 [/SUP]
Affiliations
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.
. 2023 Jan 13;14(1):199.
doi: 10.1038/s41467-023-35928-z.
Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation
Thiago Moreno L Souza[SUP] #[/SUP][SUP] 1 2 [/SUP], Vagner D Pinho[SUP] 3 [/SUP], Cristina F Setim[SUP] 4 [/SUP], Carolina Q Sacramento[SUP] 5 6 [/SUP], Rodrigo Marcon[SUP] 4 [/SUP], Natalia Fintelman-Rodrigues[SUP] 5 6 [/SUP], Otavio A Chaves[SUP] 5 6 [/SUP], Melina Heller[SUP] 4 [/SUP], Jairo R Temerozo[SUP] 5 7 8 [/SUP], André C Ferreira[SUP] 5 6 9 [/SUP], Mayara Mattos[SUP] 5 6 [/SUP], Patrícia B Momo[SUP] 3 [/SUP], Suelen S G Dias[SUP] 5 [/SUP], João S M Gesto[SUP] 5 6 [/SUP], Filipe Pereira-Dutra[SUP] 5 [/SUP], João P B Viola[SUP] 10 [/SUP], Celso Martins Queiroz-Junior[SUP] 11 [/SUP], Lays Cordeiro Guimarães[SUP] 12 [/SUP], Ian Meira Chaves[SUP] 11 [/SUP], Pedro Pires Goulart Guimarães[SUP] 12 [/SUP], Vivian Vasconcelos Costa[SUP] 11 [/SUP], Mauro Martins Teixeira[SUP] 11 [/SUP], Dumith Chequer Bou-Habib[SUP] 7 8 [/SUP], Patrícia T Bozza[SUP] 5 [/SUP], Anderson R Aguillón[SUP] 3 [/SUP], Jarbas Siqueira-Junior[SUP] 4 [/SUP], Sergio Macedo-Junior[SUP] 4 [/SUP], Edineia L Andrade[SUP] 4 [/SUP], Guilherme P Fadanni[SUP] 4 [/SUP], Sara E L Tolouei[SUP] 4 [/SUP], Francine B Potrich[SUP] 4 [/SUP], Adara A Santos[SUP] 4 [/SUP], Naiani F Marques[SUP] 4 [/SUP], João B Calixto[SUP] #[/SUP][SUP] 13 [/SUP], Jaime A Rabi[SUP] #[/SUP][SUP] 14 [/SUP]
Affiliations
- PMID: 36639383
- DOI: 10.1038/s41467-023-35928-z
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.