Antiviral Research, volume 206, pages 105402

Broad-spectrum antiviral diazadispiroalkane core molecules block attachment and cell-to-cell spread of herpesviruses

Dohme Annika 1
1
 
Charité-Universitätsmedizin Berlin, Institute of Virology, Berlin, Germany
Publication typeJournal Article
Publication date2022-10-01
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor7.6
ISSN01663542, 18729096
Pharmacology
Virology
Abstract
Regarding the problems with the current available drugs many research studies deal with the class of the dispirotripiperazine (DSTP)-based compounds. These are small molecules consisting of polycyclic saturated ring systems with positively charged nitrogen atoms. These compounds can interact with negatively charged HSPGs and thus block viral attachment. In a previous paper by Adfeldt et al. (2021), we have shown that the diazadispiroalkane derivatives 11826091 and 11826236 exhibit dose-dependent antiviral activity against human cytomegalovirus (HCMV) and pseudorabies virus (PrV). In the present study, these two small molecules are evaluated against two other herpesvirus species, murine cytomegalovirus (MCMV) and herpes simplex virus type 1 (HSV-1), as well as a HCMV clinical isolate. They exhibit potent antiherpetic activity against these herpesviruses with a high selectivity index. The low cytotoxicity was underlined by the LD 50 determination in mice. We have shown that inhibition occurs at an early stage of infection. Interestingly, 11826091 and 11826236 reduced immediate early gene expression in HCMV and HSV-1 infected cells in a dose-dependent manner. Both small molecules probably interact electrostatically with sulfated glycosaminoglycans (GAGs) of proteoglycans on target cells resulting in blockage of adsorption sites for herpesvirus glycoprotein. Moreover, both compounds showed significant effects against the cell-associated viral spread of HSV-1 and HCMV. Overall, this study shows that 11826091 and 11826236 represent two promising candidates for a new approach of a broad antiviral therapy. • Compounds prevent viral invasion by a block of attachment and cell to cell spread. • High potency as viral entry inhibitors. • Confirmed broad-spectrum antiviral activity against herpesviruses. • Promising for development of novel antiviral therapy.

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Dohme A. Broad-spectrum antiviral diazadispiroalkane core molecules block attachment and cell-to-cell spread of herpesviruses // Antiviral Research. 2022. Vol. 206. p. 105402.
GOST all authors (up to 50) Copy
Dohme A. Broad-spectrum antiviral diazadispiroalkane core molecules block attachment and cell-to-cell spread of herpesviruses // Antiviral Research. 2022. Vol. 206. p. 105402.
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RIS Copy
TY - JOUR
DO - 10.1016/j.antiviral.2022.105402
UR - https://doi.org/10.1016%2Fj.antiviral.2022.105402
TI - Broad-spectrum antiviral diazadispiroalkane core molecules block attachment and cell-to-cell spread of herpesviruses
T2 - Antiviral Research
AU - Dohme, Annika
PY - 2022
DA - 2022/10/01 00:00:00
PB - Elsevier
SP - 105402
VL - 206
SN - 0166-3542
SN - 1872-9096
ER -
BibTex
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BibTex Copy
@article{2022_Dohme
author = {Annika Dohme},
title = {Broad-spectrum antiviral diazadispiroalkane core molecules block attachment and cell-to-cell spread of herpesviruses},
journal = {Antiviral Research},
year = {2022},
volume = {206},
publisher = {Elsevier},
month = {oct},
url = {https://doi.org/10.1016%2Fj.antiviral.2022.105402},
pages = {105402},
doi = {10.1016/j.antiviral.2022.105402}
}
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