Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Dai, Wen wen; Wu, Yu; Bi, Jin peng; Wang, Jing yu; Wang, Shuai; Kong, Wei; Barbier, Julien; Cintrat, Jean‐Christophe; Gao, Feng; Jiang, Zheng ran; Gillet, Daniel; Su, Wei heng; Jiang, Chun lai

doi:10.4014/jmb.1712.12052

Cited by 12 publications

(15 citation statements)

References 49 publications

(89 reference statements)

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“…In the natural environment, the main host of HSV infection is human, but it has a full susceptibility to infect cells in the laboratory environment. Previous literatures [32,33] have shown that HSV-2 infection models in vitro can be established on various cell lines, such as human embryonic lung fibroblasts (MRC-5), human endometrial adenocarcinoma cells (HEC-1-A), human cervical cancer cells (Hela), human lung cancer cells (A549), African green monkey kidney cells (Vero), and milk hamster kidney cells (BHK). Among them, Vero cells are classic cell lines for virus amplification.…”

Section: Discussionmentioning

confidence: 99%

Antiviral mechanism of carvacrol on HSV-2 infectivity through inhibition of RIP3-mediated programmed cell necrosis pathway and ubiquitin-proteasome system in BSC-1 cells

Wang

et al. 2020

BMC Infect Dis

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Background Carvacrol, as the major components of aromatic plants used for treating human skin diseases including origanum, Satureja, thymus, and coridothymus species, presented a kind of antiviral activity. To explore the mechanisms of carvacrol against herpes simplex virus (HSV) in vitro. Method The BSC-1 cells model of HSV infection was established, and from the two aspects of viral replication level and cell death pathway, the antiviral effects of carvacrol on HSV infected cells were also evaluated by plaque assay under the three modes including prevention, treatment, and direct inactivation. Results In the three ways, the half-maximal effective concentration (EC50) of 2% true carvacrol solution on HSV-2 infected cells were severally 0.43, 0.19 and 0.51 mmol/L, and the corresponding therapeutic index (TI) were 4.02, 9.11 and 3.39, respectively. It’s the opposite of the increased levels caused by HSV-2 infection, that both the expressions at the transcription genes and protein levels of virus own replication key factors (including ICP4, ICP27, VP16, gB, and UL30) and cytokines (including RIP3, TNF-α, and MLKL) of infected cells treated with carvacrol were dose-dependently inhibited. Besides, HSV-2 infection can cause the decrease of intracellular protein ubiquitination level, and carvacrol can reverse the ubiquitination decrease level caused by HSV-2 infection. Conclusion Carvacrol exhibits significant antiviral activity by inhibiting the HSV-2 proliferation process and HSV-2-induced TNF-α increasing levels, decreasing RIP3 and MLKL protein expressions through the intracellular RIP3-mediated programmed cell necrosis pathway. In addition, carvacrol also may exhibit anti-HSV-2 activity by reversing the ubiquitination decrease level caused by HSV-2 infection on the ubiquitin-proteasome system, which provides insights into the molecular mechanism.

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Section: Discussionmentioning

confidence: 99%

Antiviral mechanism of carvacrol on HSV-2 infectivity through inhibition of RIP3-mediated programmed cell necrosis pathway and ubiquitin-proteasome system in BSC-1 cells

Wang

et al. 2020

BMC Infect Dis

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“…We and others have previously shown that Retro-2 and its analogs can reduce Leishmania, polyomavirus, and papillomavirus infections, as well as inhibit Shiga toxin trafficking in cells (Noel et al, 2013;Carney et al, 2014;Craig et al, 2017). Recent reports have also investigated the effect of Retro-2 derivatives on HSV2 infections (Dai et al, 2018). A majority of these studies have focused primarily on Retro-2 derivatives, and at present, less is understood about the antipathogenic potential of Retro-1 and its derivatives.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity

et al. 2020

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Orthopoxviruses (OPXVs) are an increasing threat to human health due to the growing population of OPXV-naive individuals after the discontinuation of routine smallpox vaccination. Antiviral drugs that are effective as postexposure treatments against variola virus (the causative agent of smallpox) or other OPXVs are critical in the event of an OPXV outbreak or exposure. The only US Food and Drug Administration-approved drug to treat smallpox, Tecovirimat (ST-246), exerts its antiviral effect by inhibiting extracellular virus (EV) formation, thereby preventing cell-cell and long-distance spread. We and others have previously demonstrated that host Golgi-associated retrograde proteins play an important role in monkeypox virus (MPXV) and vaccinia virus (VACV) EV formation. Inhibition of the retrograde pathway by small molecules such as Retro-2 has been shown to decrease VACV infection in vitro and to a lesser extent in vivo. To identify more potent inhibitors of the retrograde pathway, we screened a large panel of compounds containing a benzodiazepine scaffold like that of Retro-1, against VACV infection. We found that a subset of these compounds displayed better anti-VACV activity, causing a reduction in EV particle formation and viral spread compared to Retro-1. PA104 emerged as the most potent analog, inhibiting 90% viral spread at 1.3 µM with a high selectivity index. In addition, PA104 strongly inhibited two distinct ST-246resistant viruses, demonstrating its potential benefit for use in combination therapy with ST-246. These data and further characterizations of the specific protein targets and in vivo efficacy of PA104 may have important implications for the design of effective antivirals against OPXV.

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“…Recent elegant studies have surprisingly revealed that Retro-2 indeed affects ER functions, which in turn affects trafficking events at the EE/TGN interface (Morgens et al, 2019;Forrester et al, 2020). However, observations that Retro-2 blocks the entry of several viruses at the cell membrane (Dai et al, 2018;Shtanko et al, 2018), in which Stx5 is not expressed, suggest that the small compound additionally exerts Stx5-independent inhibitory effects at sites other than the EE/TGN and ER. Our results reveal that the MT network is a new ER/Golgi-independent cellular target of Retro-2.…”

Section: Discussionmentioning

confidence: 99%

Small Trafficking Inhibitor Retro-2 Disrupts the Microtubule-Dependent Trafficking of Autophagic Vacuoles

Nicolas

Moal

2020

Front. Cell Dev. Biol.

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Autophagy is a catabolic recycling process by which a cell degrades its own constituents to contribute to cell homeostasis or survival. We report that the small trafficking inhibitor Retro-2 impairs microtubule-dependent vacuolar trafficking in autophagy. Retro-2 induced autophagy and promoted the dramatic cytoplasmic accumulation of large autophagosomes. Moreover, Retro-2 decreased the spreading of autophagosomes within the cytoplasm of nutrient-starved cells. In addition, Retro-2 abolished autolysosomes formation. We show that these effects arise from hitherto unsuspected disassembly activity of the small molecule on the cellular microtubule network, which is known to act as a key regulator of vacuolar trafficking of the autophagy pathway.

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Antiviral Effect of Retro-2.1 against Herpes Simplex Virus Type 2 In Vitro

Cited by 12 publications

References 49 publications

Antiviral mechanism of carvacrol on HSV-2 infectivity through inhibition of RIP3-mediated programmed cell necrosis pathway and ubiquitin-proteasome system in BSC-1 cells

Antiviral mechanism of carvacrol on HSV-2 infectivity through inhibition of RIP3-mediated programmed cell necrosis pathway and ubiquitin-proteasome system in BSC-1 cells

Discovery of Retro-1 Analogs Exhibiting Enhanced Anti-vaccinia Virus Activity

Small Trafficking Inhibitor Retro-2 Disrupts the Microtubule-Dependent Trafficking of Autophagic Vacuoles

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