Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation
Year: 2023
Type: article
Abstract: Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are still scarce and the emergence of new variants challenging immunized individuals, suggests that mutant viruses might also emerge because of antiviral pressure. Therefore, beyond the recently alleged positive antiviral clinical results with molnupiravir™ and paxlovid™, the continuous search for drugs against 2019 coronavirus disease (COVID-19) is necessary. Because severe COVID-19 is a virus-triggered immune and inflammatory disfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that N6-furfurylaminopurine (kinetin, MB-905) inhibits the in vitro replication of SARS-CoV-2 at the sub-micromolar range in human hepatic and pulmonary cell lines. On infected monocytes, MB-905 reduced virus replication, IL-6 and TNFα levels. As a pro-drug, MB-905 is converted into its triphosphate nucleotide to inhibit viral RNA synthesis and induce an error-prone virus replication. Consistently, co-inhibition of SARS-CoV-2 exonuclease, a proofreading enzyme that corrects erroneously placed nucleotides during viral RNA replication, potentiated the inhibitory effect of MB-905. SARS-CoV-2-infected transgenic mice expressing human ACE2 were treated with MB-905 and decreased viral replication of the gamma variant was observed, along with reduced lung necrosis, hemorrhage and inflammation, together with increasedmice survival. MB-905 showed good oral absorption, its metabolites were stable and achieved long-lasting plasma concentrations exceeding those required for the in vitro inhibition. Besides, MB-905 was neither mutagenic, toxic during chronic treatment, nor cardiotoxic. Because kinetin has already been clinically investigated for a rare genetic disease at regimens that are beyond the predicted concentrations of antiviral/anti-inflammatory inhibition demonstrated here, our investigation strongly suggests the opportunity for a rapid clinical development of a new and orally available antiviral substance for the treatment of COVID-19.
Source: Nature Communications
Authors: Thiago Moreno L. Souza, Vagner D. Pinho, Cristina F. Setim, Carolina Q. Sacramento, Rodrigo Marcon, Natalia Fintelman-Rodrigues, Otavio A. Chaves, Melina Heller, Jairo R. Temerozo, André C. Ferreira, Mayara Mattos, Patrícia B. Momo, Suelen S. G. Dias, João S. M. Gesto, Filipe Pereira-Dutra, João P. B. Viola, Celso Martins Queiroz-Junior, Lays Cordeiro Guimarães, Ian Meira Chaves, Pedro Pires Goulart Guimarães, Vivian Vasconcelos Costa, Mauro Martins Teixeira, Dumith Chequer Bou-Habib, Patrícia T. Bozza, Anderson R. Aguillón, Jarbas Siqueira-Junior, Sergio Macedo-Junior, Edineia L. Andrade, Guilherme P. Fadanni, Sara E. L. Tolouei, Francine B. Potrich, Adara A. Santos, Naiani F. Marques, João B. Calixto, Jaime A. Rabi
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Ministério da Ciência, Tecnologia e Inovação, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Institut National Du Cancer, Fundação Oswaldo Cruz, Universidade Federal de Minas Gerais, Universidade Federal do Rio de Janeiro, Empresa Brasileira de Pesquisa e Inovação Industrial, National Cancer Institute
OpenAlex ID: W4315865871