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 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.

In vivo/in vitro studies of the effects of the type II arabinogalactan isolated from Maytenus ilicifolia Mart. ex Reissek on the gastrointestinal tract of rats.

Type II arabinogalactan (AG) is a polysaccharide found in Maytenus ilicifolia (Celastraceae), a plant reputed as gastroprotective. Oral and intraperitoneal administration of the AG protected rats from gastric ulcers induced by ethanol. No alteration of mechanisms related to acid gastric secretion and gastrointestinal motility were observed. In vitro, the AG showed a potent scavenging activity against the radical of DPPH (2,2-diphenyl-1-picrylhydrazyl) with an IC50 value of 9.3 microM. However, the mechanism of the gastroprotective action remains to be identified.