Identification and preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral and anti-inflammatory therapy
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..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
ResearchSquare.com - (2023) vom: 14. Jan. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Souza, Thiago [VerfasserIn] |
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| doi: |
10.21203/rs.3.rs-1533971/v1 |
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| PPN (Katalog-ID): |
XRA035704136 |
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| 520 | |a 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. | ||
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