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 # 1 2 , Vagner D Pinho 3 , Cristina F Setim 4 , Carolina Q Sacramento 5 6 , Rodrigo Marcon 4 , Natalia Fintelman-Rodrigues 5 6 , Otavio A Chaves 5 6 , Melina Heller 4 , Jairo R Temerozo 5 7 8 , André C Ferreira 5 6 9 , Mayara Mattos 5 6 , Patrícia B Momo 3 , Suelen S G Dias 5 , João S M Gesto 5 6 , Filipe Pereira-Dutra 5 , João P B Viola 10 , Celso Martins Queiroz-Junior 11 , Lays Cordeiro Guimarães 12 , Ian Meira Chaves 11 , Pedro Pires Goulart Guimarães 12 , Vivian Vasconcelos Costa 11 , Mauro Martins Teixeira 11 , Dumith Chequer Bou-Habib 7 8 , Patrícia T Bozza 5 , Anderson R Aguillón 3 , Jarbas Siqueira-Junior 4 , Sergio Macedo-Junior 4 , Edineia L Andrade 4 , Guilherme P Fadanni 4 , Sara E L Tolouei 4 , Francine B Potrich 4 , Adara A Santos 4 , Naiani F Marques 4 , João B Calixto # 13 , Jaime A Rabi # 14
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.