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

[tetano]

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.