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

• Published in: Nature communications Vol. 14; no. 1; pp. 199 - 17
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 38/23; 38/77; 38/88; 38/91; 59; 631/154/436/2388; 631/326/596/1296; 631/326/596/4130; 631/45/500; 64/86; 9/25; Animals; Anti-inflammatory agents; Antiviral agents; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Cell lines; Coronaviruses; COVID-19; Editing; Exonuclease; Genetic disorders; Hamsters; Hemorrhage; Humanities and Social Sciences; Humans; Immune response (humoral); Immunization; Inflammation; Inflammation - drug therapy; Interleukin 6; Kinetin; Kinetin - pharmacology; Lungs; Metabolites; Mice; Monocytes; multidisciplinary; Necrosis; Nucleotides; Proofreading; Replication; Ribonucleic acid; RNA; SARS-CoV-2; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Transcription; Tumor necrosis factor-α; Viral diseases; Virus Replication; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-35928-z

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. The search for antivirals against SARS-CoV-2 continue due to the emergence of variants of concerns, able to escape the vaccinal humoral response. In this work, authors pre-clinically explore the potential of kinetin against SARS-CoV-2, which could be used alone or in combination with other antivirals.