Please use this identifier to cite or link to this item:
Type
ArticleCopyright
Open access
Collections
- IOC - Artigos de Periódicos [12879]
Metadata
Show full item record
THE ROLE OF PYRAZOLOPYRIDINE DERIVATIVES ON DIFFERENT STEPS OF HERPES SIMPLEX VIRUS TYPE-1 IN VITRO REPLICATIVE CYCLE
Author
Affilliation
Abstract
Herpes simplex virus type-1 (HSV-1) infection causes several disorders, and acyclovir is
used as a reference compound. However, resistant strains are commonly observed. Herein, we
investigate the effects of N-heterocyclic compounds (pyrazolopyridine derivatives), named ARA-04,
ARA-05, and AM-57, on HSV-1 in vitro replication. We show that the 50% effective concentration
(EC50) values of the compounds ARA-04, ARA-05, and AM-57 were 1.00 0.10, 1.00 0.05, and
0.70 0.10 M, respectively. These compounds presented high 50% cytotoxic concentration (CC50)
values, which resulted in a selective index (SI) of 1000, 1000, and 857.1 for ARA-04, ARA-05, and
AM-57, respectively. To gain insight into which step of the HSV-1 replication cycle these molecules
would impair, we performed adsorption and penetration inhibition assays and time-of-addition
experiments. Our results indicated that ARA-04 and ARA-05 affected viral adsorption, while AM-57
interfered with the virus replication during its - and
-phases and decreased ICP27 content during
initial and late events of HSV-1 replication. In addition, we also observed that AM-57 caused a
strong decrease in viral gD content, which was reinforced by in silico calculations that suggested
AM-57 interacts preferentially with the viral complex between a general transcription factor and
virion protein (TFIIBc-VP16). In contrast, ARA-04 and ARA-05 interact preferentially in the proteins
responsible for the viral adsorption process (nectin-1 and glycoprotein). Thus, our results suggest
that the 1H-pyrazolo[3,4-b]pyridine derivatives inhibit the HSV-1 replicative cycle with a novel
mechanism of action, and its scaffold can be used as a template for the synthesis of promising new molecules with antiviral effects, including to reinforce the presented data herein for a limited number
of molecules.
Share