Inhibitory Effect of PIK-24 on Respiratory Syncytial Virus Entry by Blocking Phosphatidylinositol-3 Kinase Signaling

Abstract

Phosphoinositide-3 kinase signaling modulates many cellular processes including cell survival, proliferation, differentiation, and apoptosis. Currently, it is known that the establishment of respiratory syncytial virus infection requires phosphoinositide-3 kinase signaling. However, the regulatory pattern of phosphoinositide-3 kinase signaling or its corresponding molecular mechanism during respiratory syncytial virus entry remains unclear. Here, the involvement of phosphoinositide-3 kinase signaling in respiratory syncytial virus entry was studied. PIK-24, a novel compound designed with phosphoinositide-3 kinase as a target, had a potent anti-respiratory syncytial virus activity both in vitro and in vivo. PIK-24 significantly reduced viral entry into the host cell through blocking the late stage of the fusion process. In a mouse model, PIK-24 effectively reduced the viral load and alleviated inflammation in lung tissue. Subsequent studies on the antiviral mechanism of PIK-24 revealed that viral entry was accompanied by phosphoinositide-3 kinase signaling activation, downstream RhoA and cofilin upregulation, and actin cytoskeleton rearrangement. PIK-24 treatment significantly reversed all these effects. The disruption of actin cytoskeleton dynamics or the modulation of phosphoinositide-3 kinase activity by knockdown also affected viral entry efficacy. Altogether, it is reasonable to conclude that the antiviral activity of PIK-24 depends on the phosphoinositide-3 kinase signaling and the use of phosphoinositide-3 kinase signaling to regulate actin cytoskeleton rearrangement plays a key role in respiratory syncytial virus entry.

RNA-RNA interactions between Respiratory syncytial virus and miR-26 and miR-27 are associated with regulation of cell cycle and antiviral immunity

“…We use the identification of 396 high confidence targets by CLEAR-CLIP combined with gene expression analysis of miR-27 modulated cells to systematically demonstrate the functionality of targets of miR-27 detected in our study in lung epithelial cells. We show that the inhibition of miR-27 activity by RSV is associated with upregulation of pathways important for RSV infection and replication including PI3K/Akt and MAPK signalling as well as control of cell cycle (67,(77)(78)(79)(80)(81)(82)(83). In addition, we identify as direct miR-27 targets the cytokine CSF1 as well as the chemokine CXCL2 which play important roles in intercellular communication (84).…”

An overview on the RSV-mediated mechanisms in the onset of non-allergic asthma

“…Several studies reported that the viral penetration into host cells depends on PI3K signaling activation, and the PI3K activity requires, in turn, the activation of RhO-family GTPases and actin cytoskeleton reorganization. The role of the PI3K signaling results from the evidence that an impaired activity or inhibition of PI3K affects RSV replication ( 31 ).…”

Discovery of rhodomyrtone as a broad-spectrum antiviral inhibitor with anti-SARS-CoV-2 activity

“…CC-BY-NC-ND 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted November 16, 2020. ; https://doi.org/10.1101/2020.11.14.382770 doi: bioRxiv preprint 4 series of compounds were found to exhibit potent antiviral activities [6][7][8][9][10] . In this paper, we report a plant-derived small molecule, 6,8-dihydroxy-9-isobutyl-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-4,9-dihydro-1H-…”

“…As an ongoing research interest of our group in the past decades, we have constructed an in-house compound library composing of structural diversity natural products obtained from approximately 100 species of medicinal plants. After systematic bioassay screening, a series of compounds were found to exhibit potent antiviral activities 6–10 . In this paper, we report a plant-derived small molecule, 6,8-dihydroxy-9-isobutyl-2,2,4,4-tetramethyl-7-(3-methylbutanoyl)-4,9-dihydro-1 H -xanthene-1,3(2 H )-dione (rhodomyrtone, Fig.…”