Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2.
Sci Rep
; 13(1): 1639, 2023 01 30.
Article
in English
| MEDLINE | ID: covidwho-2221863
ABSTRACT
The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Interferon Type I
/
Herpesvirus 1, Human
/
Amaryllidaceae Alkaloids
/
Antineoplastic Agents
Type of study:
Prognostic study
Limits:
Animals
Language:
English
Journal:
Sci Rep
Year:
2023
Document Type:
Article
Affiliation country:
S41598-023-28691-0
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