Abstract
Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50 μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of 'quiescent' HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 16-23 |
| Number of pages | 8 |
| Journal | Antiviral Research |
| Volume | 121 |
| DOIs | |
| State | Published - Jun 29 2015 |
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Keywords
- Antiviral
- Herpes simplex virus type 1
- HSV
- Human cytomegalovirus
- Induced pluripotent stem cells
- Varicella zoster virus
ASJC Scopus subject areas
- Virology
- Pharmacology
Cite this
Broad-spectrum non-nucleoside inhibitors of human herpesviruses. / McClain, Lora; Zhi, Yun; Cheng, Hoyee; Ghosh, Ayantika; Piazza, Paolo; Yee, Michael B.; Kumar, Santosh; Milosevic, Jadranka; Bloom, David C.; Boger, Ravit; Kinchington, Paul R.; Yolken, Robert H; Nimgaonkar, Vishwajit; D'Aiuto, Leonardo.
In: Antiviral Research, Vol. 121, 29.06.2015, p. 16-23.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Broad-spectrum non-nucleoside inhibitors of human herpesviruses
AU - McClain, Lora
AU - Zhi, Yun
AU - Cheng, Hoyee
AU - Ghosh, Ayantika
AU - Piazza, Paolo
AU - Yee, Michael B.
AU - Kumar, Santosh
AU - Milosevic, Jadranka
AU - Bloom, David C.
AU - Boger, Ravit
AU - Kinchington, Paul R.
AU - Yolken, Robert H
AU - Nimgaonkar, Vishwajit
AU - D'Aiuto, Leonardo
PY - 2015/6/29
Y1 - 2015/6/29
N2 - Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50 μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of 'quiescent' HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo.
AB - Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50 μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of 'quiescent' HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo.
KW - Antiviral
KW - Herpes simplex virus type 1
KW - HSV
KW - Human cytomegalovirus
KW - Induced pluripotent stem cells
KW - Varicella zoster virus
UR - http://www.scopus.com/inward/record.url?scp=84933565947&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84933565947&partnerID=8YFLogxK
U2 - 10.1016/j.antiviral.2015.06.005
DO - 10.1016/j.antiviral.2015.06.005
M3 - Article
C2 - 26079681
AN - SCOPUS:84933565947
VL - 121
SP - 16
EP - 23
JO - Antiviral Research
JF - Antiviral Research
SN - 0166-3542
ER -