Mechanisms of antiviral activity of the new hDHODH inhibitor MEDS433 against respiratory syncytial virus replication.

Autor: Luganini A; Department of Life Sciences and Systems Biology, University of Torino, 10123, Torino, Italy., Sibille G; Department of Life Sciences and Systems Biology, University of Torino, 10123, Torino, Italy., Pavan M; Department of Life Sciences and Systems Biology, University of Torino, 10123, Torino, Italy., Mello Grand M; Fondazione Edo ed Elvo Tempia, 13900, Biella, Italy., Sainas S; Department of Drug Sciences and Technology, University of Torino, 10125, Torino, Italy., Boschi D; Department of Drug Sciences and Technology, University of Torino, 10125, Torino, Italy., Lolli ML; Department of Drug Sciences and Technology, University of Torino, 10125, Torino, Italy., Chiorino G; Fondazione Edo ed Elvo Tempia, 13900, Biella, Italy., Gribaudo G; Department of Life Sciences and Systems Biology, University of Torino, 10123, Torino, Italy. Electronic address: giorgio.gribaudo@unito.it.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2023 Nov; Vol. 219, pp. 105734. Date of Electronic Publication: 2023 Oct 16.
DOI: 10.1016/j.antiviral.2023.105734
Abstrakt: Human respiratory syncytial virus (RSV) is an important cause of acute lower respiratory infections, for which no effective drugs are currently available. The development of new effective anti-RSV agents is therefore an urgent priority, and Host-Targeting Antivirals (HTAs) can be considered to target RSV infections. As a contribution to this antiviral avenue, we have characterized the molecular mechanisms of the anti-RSV activity of MEDS433, a new inhibitor of human dihydroorotate dehydrogenase (hDHODH), a key cellular enzyme of de novo pyrimidine biosynthesis. MEDS433 was found to exert a potent antiviral activity against RSV-A and RSV-B in the one-digit nanomolar range. Analysis of the RSV replication cycle in MEDS433-treated cells, revealed that the hDHODH inhibitor suppressed the synthesis of viral genome, consistently with its ability to specifically target hDHODH enzymatic activity. Then, the capability of MEDS433 to induce the expression of antiviral proteins encoded by Interferon-Stimulated Genes (ISGs) was identified as a second mechanism of its antiviral activity against RSV. Indeed, MEDS433 stimulated secretion of IFN-β and IFN-λ1 that, in turn, induced the expression of some ISG antiviral proteins, such as IFI6, IFITM1 and IRF7. Singly expression of these ISG proteins reduced RSV-A replication, thus likely contributing to the overall anti-RSV activity of MEDS433. Lastly, MEDS433 proved to be effective against RSV-A replication even in a primary human small airway epithelial cell model. Taken as a whole, these observations provide new insights for further development of MEDS433, as a promising candidate to develop new strategies for treatment of RSV infections.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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