Back to Search
Start Over
Dopamine and its precursor levodopa inactivate SARS-CoV-2 main protease by forming a quinoprotein.
- Source :
-
Free Radical Biology & Medicine . Aug2024, Vol. 220, p167-178. 12p. - Publication Year :
- 2024
-
Abstract
- Many studies show either the absence, or very low levels of, SARS-CoV-2 viral RNA and/or antigen in the brain of COVID-19 patients. Reports consistently indicate an abortive infection phenomenon in nervous cells despite the fact that they contain the SARS-CoV-2 receptor, ACE2. Dopamine levels in different brain regions are in the range of micromolar to millimolar concentrations. We have shown that sub-micromolar to low micromolar concentrations of dopamine or its precursor (levodopa) time- and dose-dependently inhibit the activity of SARS-CoV-2 main protease (Mpro), which is vital for the viral life cycle, by forming a quinoprotein. Thiol detection coupled with the assessment of Mpro activity suggests that among the 12 cysteinyl thiols, the active site, Cys145-SH, is preferentially conjugated to the quinone derived from the oxidation of dopamine or levodopa. LC-MS/MS analyses show that the Cys145-SH is covalently conjugated by dopamine- or levodopa- o -quinone. These findings help explain why SARS-CoV-2 causes inefficient replication in many nerve cell lines. It is well recognized that inhaled pulmonary drug delivery is the most robust therapy pathway for lung diseases. CVT-301 (orally inhaled levodopa) was approved by the FDA as a drug for Parkinson's patients prior to the outbreak of COVID-19 in 2018. Based on the fact that SARS-CoV-2 causes inefficient replication in the CNS with abundant endogenous Mpro inhibitor in addition to the current finding that levodopa has an Mpro-inhibitory effect somewhat stronger than dopamine, we should urgently investigate the use of CVT-301 as a lung-targeting, COVID-19, Mpro inhibitor. [Display omitted] • The reason SARS-CoV-2 fails to cause productive infection in many nerve cell lines is unclear. • Neurons are rich in dopamine which inhibits Mpro by forming a quinoprotein. • Dopamine- o -quinone preferentially reacts with the active site, Cys145-SH, of 12 Mpro cysteinyl thiols. • The dopamine precursor, levodopa, exhibits an inhibitory effect stronger than that of dopamine itself. • Orally inhaled levodopa (the FDA-approved CVT-301) could be repurposed as an Mpro-inhibitor of COVID-19 that targets the lung. [ABSTRACT FROM AUTHOR]
- Subjects :
- *DOPA
*DOPAMINE
*SARS-CoV-2
*DOPAMINE receptors
*PARKINSON'S disease
*COVID-19
Subjects
Details
- Language :
- English
- ISSN :
- 08915849
- Volume :
- 220
- Database :
- Academic Search Index
- Journal :
- Free Radical Biology & Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 177455446
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2024.05.008