Diazadispiroalkane Derivatives Are New Viral Entry Inhibitors.
antiviral activity
entry inhibitors
heparan sulfate binding
human cytomegalovirus
new mode of action
pseudorabies virus
virus attachment
Journal
Antimicrobial agents and chemotherapy
ISSN: 1098-6596
Titre abrégé: Antimicrob Agents Chemother
Pays: United States
ID NLM: 0315061
Informations de publication
Date de publication:
18 03 2021
18 03 2021
Historique:
received:
02
10
2020
accepted:
18
01
2021
pubmed:
27
1
2021
medline:
22
6
2021
entrez:
26
1
2021
Statut:
epublish
Résumé
Herpesviruses are widespread and can cause serious illness. Many currently available antiviral drugs have limited effects, result in rapid development of resistance, and often exhibit dose-dependent toxicity. Especially for human cytomegalovirus (HCMV), new well-tolerated compounds with novel mechanisms of action are urgently needed. In this study, we characterized the antiviral activity of two new diazadispiroalkane derivatives, 11826091 and 11826236. These two small molecules exhibited strong activity against low-passage-number HCMV. Pretreatment of cell-free virus with these compounds greatly reduced infection. Time-of-addition assays where 11826091 or 11826236 was added to cells before infection, before and during infection, or during or after infection demonstrated an inhibitory effect on early steps of infection. Interestingly, 11826236 had an effect by addition to cells after infection. Results from entry assays showed the major effect to be on attachment. Only 11826236 had a minimal effect on penetration comparable to heparin. Further, no effect on virus infection was found for cell lines with a defect in heparan sulfate expression or lacking all surface glycosaminoglycans, indicating that these small molecules bind to heparan sulfate on the cell surface. To test this further, we extended our analyses to pseudorabies virus (PrV), a member of the
Identifiants
pubmed: 33495228
pii: AAC.02103-20
doi: 10.1128/AAC.02103-20
pmc: PMC8097465
pii:
doi:
Substances chimiques
Alkanes
0
Antiviral Agents
0
Glycosaminoglycans
0
Spiro Compounds
0
Viral Envelope Proteins
0
Heparin
9005-49-6
Heparitin Sulfate
9050-30-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2021 American Society for Microbiology.
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