RESUMO
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.
Assuntos
Antivirais , COVID-19 , Animais , Humanos , Camundongos , Antivirais/farmacologia , Antivirais/uso terapêutico , SARS-CoV-2 , Cinetina/farmacologia , Inflamação/tratamento farmacológico , Nucleotídeos , Replicação ViralRESUMO
O artigo trata do desenvolvimento de um antiviral de uso oral contra a Covid-19. A substância, batizada de MB-905, foi purificada a partir da cinetina e demonstrou-se eficaz para inibir a replicação do Sars-CoV-2 em linhagens de células humanas hepáticas e pulmonares, além de auxiliar a frear o processo inflamatório desencadeado pelo vírus.