An inducible heat shock protein 70 small molecule inhibitor demonstrates anti-dengue virus activity, validating Hsp70 as a host antiviral target

Howe, Matthew K.; Speer, Brittany L.; Hughes, Philip F.; Loiselle, David R.; Vasudevan, Subhash G.; Haystead, Timothy

doi:10.1016/j.antiviral.2016.03.017

Cited by 39 publications

(30 citation statements)

References 50 publications

(67 reference statements)

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“…Comparing the role of Hsp70 in the virus life cycle of ZIKV and other flavivirus reveals the subtle interplay between viral proteins and host pro- teostasis. Like ZIKV, DENV also requires Hsp70 to facilitate virus entry and particle production (Howe et al, 2016; Taguwa et al, 2015). However, DENV requires continued Hsp70 function for vRNA synthesis, while once the ZIKV replication complex is assembled, Hsp70 inhibitors no longer affect vRNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

et al. 2019

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SUMMARY The spread of mosquito-borne Zika virus (ZIKV), which causes neurological disorders and micro-cephaly, highlights the need for countermeasures against sudden viral epidemics. Here, we tested the concept that drugs targeting host proteostasis pro-vide effective antivirals. We show that different cyto-solic Hsp70 isoforms are recruited to ZIKV-induced compartments and are required for virus replication at pre- and post-entry steps. Drugs targeting Hsp70 significantly reduce replication of different ZIKV strains in human and mosquito cells, including hu-man neural stem cells and a placental trophoblast cell line, at doses without appreciable toxicity to the host cell. By targeting several ZIKV functions, including entry, establishment of active replication complexes, and capsid assembly, Hsp70 inhibitors are refractory to the emergence of drug-resistant virus. Importantly, these drugs protected mouse models from ZIKV infection, reducing viremia, mor-tality, and disease symptoms. Hsp70 inhibitors are thus attractive candidates for ZIKV therapeutics with the added benefit of a broad spectrum of action.

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Section: Discussionmentioning

confidence: 99%

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

et al. 2019

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“…Surprisingly, labile zinc pool was restored within 2 h of removing the zinc chelator suggesting that transient zinc depletion activates the stress response involving heat shock proteins from the Hsp70 family and an antiviral state due to NF-κB activation. Interestingly, Hsp70 family members play a necessary role in dengue replication and Hsp70 has been proposed as an antiviral target (57,58). The molecular mechanism linking zinc depletion to Hsp70 remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells

et al. 2019

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Zinc is an essential micronutrient which regulates diverse physiological functions and has been shown to play a crucial role in viral infections. Zinc has a necessary role in the replication of many viruses, however, antiviral action of zinc has also been demonstrated in in vitro infection models most likely through induction of host antiviral responses. Therefore, depending on the host machinery that the virus employs at different stages of infection, zinc may either facilitate, or inhibit virus infection. In this study, we show that zinc plays divergent roles in rotavirus and dengue virus infections in epithelial cells. Dengue virus infection did not perturb the epithelial barrier functions despite the release of virus from the basolateral surface whereas rotavirus infection led to disruption of epithelial junctions. In rotavirus infection, zinc supplementation post-infection did not block barrier disruption suggesting that zinc does not affect rotavirus life-cycle or protects epithelial barriers post-infection suggesting the involvement of cellular pathways in the beneficial effect of zinc supplementation in enteric infections. Zinc depletion by N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN) inhibited dengue virus and Japanese encephalitis virus (JEV) infection but had no effect on rotavirus. Time-of-addition experiments suggested that zinc chelation affected both early and late stages of dengue virus infectious cycle and zinc chelation abrogated dengue virus RNA replication. We show that transient zinc chelation induces ER stress and antiviral response by activating NF-kappaB leading to induction of interferon signaling. These results suggest that modulation of zinc homeostasis during virus infection could be a component of host antiviral response and altering zinc homeostasis may act as a potent antiviral strategy against flaviviruses.

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“…Due to the involvement of Hsp70 in the infection processes of multiple viruses, it has been suggested that this protein may be a potential molecular target for anti-viral therapies. 39-41 In particular, the association between Hsp70 and ZIKV suggests a critical role for this interaction during the viral infection and/or replication process. Our data suggest that Hsp70 is one of several critical factors mediating the initial entry of ZIKV into host cells.…”

Section: Discussionmentioning

confidence: 99%

Heat shock protein 70 (Hsp70) is involved in the Zika virus cellular infection process

Pujhari

et al. 2017

Preprint

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Zika virus (ZIKV) is a historically neglected flavivirus that has recently caused epidemics in the western hemisphere. ZIKV has been associated with severe symptoms including infant microcephaly and Guillain Barré syndrome, stimulating interest in understanding factors governing ZIKV infection. Heat shock protein 70 (Hsp70) has been shown to be an infection factor for multiple viruses. We investigated the role of Hsp70 in the ZIKV infection process. We localized Hsp70 protein to the Vero cell membrane surface by confocal microscopy and demonstrated that, inside the cell, there is significant co-localization between Hsp70 and ZIKV E protein. Inducing and suppressing Hsp70 expression increased and decreased ZIKV production, respectively. Antibody blocking cell surface-localized Hsp70 decreased ZIKV cell infection rates and production of infectious virus particles, as did competition with recombinant Hsp70 protein. Our data suggest that Hsp70 is an important factor in the ZIKV infection process. Understanding the interactions between Hsp70 and ZIKV may lead to novel therapeutics for ZIKV infection, particularly for pregnant women and fetuses.

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An inducible heat shock protein 70 small molecule inhibitor demonstrates anti-dengue virus activity, validating Hsp70 as a host antiviral target

Cited by 39 publications

References 50 publications

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells

Heat shock protein 70 (Hsp70) is involved in the Zika virus cellular infection process

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