The combination of levodopa with levodopa-metabolizing enzyme inhibitors prevents severe fever with thrombocytopenia syndrome virus infection in vitro more effectively than single levodopa

Elsevier

Available online 3 March 2023

Journal of Infection and ChemotherapyAuthor links open overlay panel, , , , , , , , Abstract

Severe fever with thrombocytopenia syndrome is a hemorrhagic fever caused by a tick-borne infection. The causative agent, Dabie bandavirus, is also called the severe fever with thrombocytopenia syndrome virus (SFTSV). Ogawa et al. (2022) reported that levodopa, an antiparkinsonian drug with an o-dihydroxybenzene backbone, which is important for anti-SFTSV activity, inhibited SFTSV infection. Levodopa is metabolized by dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) in vivo. We evaluated the anti-SFTSV efficacy of two DDC inhibitors, benserazide hydrochloride and carbidopa, and two COMT inhibitors, entacapone and nitecapone, which also have an o-dihydroxybenzene backbone. Only DDC inhibitors inhibited SFTSV infection with pretreatment of the virus (half-maximal inhibitory concentration [IC50]: 9.0–23.6 μM), whereas all the drugs inhibited SFTSV infection when infected cells were treated (IC50: 21.3–94.2 μM). Levodopa combined with carbidopa and/or entacapone inhibited SFTSV infection in both conditions: pretreatment of the virus (IC50: 2.9–5.8 μM) and treatment of infected cells (IC50: 10.7–15.4 μM). The IC50 of levodopa in the above-mentioned study for pretreatment of the virus and treatment of infected cells were 4.5 and 21.4 μM, respectively. This suggests that a synergistic effect was observed, especially for treatment of infected cells, although the effect is unclear for pretreatment of the virus. This study demonstrates the anti-SFTSV efficacy of levodopa-metabolizing enzyme inhibitors in vitro. These drugs may increase the time for which the levodopa concentration is maintained in vivo. The combination of levodopa and levodopa-metabolizing enzyme inhibitors might be a candidate for drug repurposing.

Section snippetsAuthorship statement

All authors meet the ICMJE authorship criteria.

MO and MF conceptualized and designed the study. MO, MM, TM, RG, and TI conducted the experiments. All authors contributed to the analysis and interpretation of data. MO and MF drafted the manuscript. All authors critically reviewed and approved the final version of the manuscript.

Funding

This study was supported by research grants for Reemerging Infectious Diseases from the Japan Agency for Medical Research and Development (AMED) [Grant Nos. 21fk0108081j0803 and 22fk0108625j0501 to MF]; research grants for Infectious Diseases Research and Infrastructure (Interdisciplinary Cutting-edge Research) from AMED [Grant Nos. 21wm0325032j0201, 22wm0325032j0202, and 21fk0108565j0101 to MF]; and partly by a Research Grant from the All Japan Coffee Association.

Declaration of competing interest

None.

Acknowledgments

We thank Dr. Charles M. Rice and Francis V. Chisari for providing the parental lines of the Huh7.5.1–8 cells. We thank Ms. Mieko Utsugi and Yoko Inamori for their technical assistance.

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© 2023 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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