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

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 TNF alpha 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.

Automated summary

The study found that MB-905 (kinetin) can inhibit the replication of SARS-CoV-2 in human hepatic and pulmonary cell lines, as well as reduce virus replication and inflammatory markers in infected monocytes. MB-905 inhibits viral RNA synthesis and induces error-prone virus replication. In addition, inhibiting the SARS-CoV-2 exonuclease enhances the inhibitory effect of MB-905. The drug shows good oral absorption, stability, and long-lasting concentrations in plasma and lung tissue, with no mutagenic or cardiotoxic effects. Animal experiments demonstrate that MB-905 decreases viral replication, lung damage, hemorrhage, and inflammation. The clinical investigation of kinetin for a rare genetic disease suggests the potential for rapid development of a new antiviral treatment for COVID-19. Ongoing research on antivirals against SARS-CoV-2 is necessary due to the emergence of variant strains that can evade vaccine-induced immunity.