An Inducible Heat Shock Protein 70 Small Molecule Inhibitor Demonstrates Anti-dengue Virus Activity, Validating Hsp70 As a Host Antiviral Target

Overview

Journal Antiviral Res

Publisher Elsevier

Date 2016 Apr 9

PMID 27058774

Citations 20

Authors

Matthew K Howe

Brittany L Speer

Philip F Hughes

David R Loiselle

Subhash Vasudevan

Timothy A J Haystead

Affiliations

Soon will be listed here.

Abstract

An estimated three billion people are at risk of Dengue virus (DENV) infection worldwide and there are currently no approved therapeutic interventions for DENV infection. Due to the relatively small size of the DENV genome, DENV is reliant on host factors throughout the viral life cycle. The inducible form of Heat Shock Protein 70 (Hsp70i) has been implicated as a host factor in DENV pathogenesis, however the complete role remains to be elucidated. Here we further illustrate the importance of Hsp70i in dengue virus pathogenesis and describe the antiviral activity of the allosteric small molecule inhibitor that is selective for Hsp70i, called HS-72. In monocytes, Hsp70i is expressed at low levels preceding DENV infection, but Hsp70i expression is induced upon DENV infection. Targeting Hsp70i with HS-72, results in a dose dependent reduction in DENV infected monocytes, while cell viability was maintained. HS-72 works to reduce DENV infection by inhibiting the entry stage of the viral life cycle, through disrupting the association of Hsp70i with the DENV receptor complex. This work highlights Hsp70i as an antiviral target and HS-72 as a potential anti-DENV therapeutic agent.

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References

Barrott J, Hughes P, Osada T, Yang X, Hartman Z, Loiselle D . Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells. Chem Biol. 2013; 20(9):1187-97. PMC: 3815696. DOI: 10.1016/j.chembiol.2013.08.004. View

Sessions O, Barrows N, Souza-Neto J, Robinson T, Hershey C, Rodgers M . Discovery of insect and human dengue virus host factors. Nature. 2009; 458(7241):1047-50. PMC: 3462662. DOI: 10.1038/nature07967. View

Mayer M . Recruitment of Hsp70 chaperones: a crucial part of viral survival strategies. Rev Physiol Biochem Pharmacol. 2004; 153:1-46. DOI: 10.1007/s10254-004-0025-5. View

Leow C, Chesebrough J, Coffman K, Fazenbaker C, Gooya J, Weng D . Antitumor efficacy of IPI-504, a selective heat shock protein 90 inhibitor against human epidermal growth factor receptor 2-positive human xenograft models as a single agent and in combination with trastuzumab or lapatinib. Mol Cancer Ther. 2009; 8(8):2131-41. DOI: 10.1158/1535-7163.MCT-08-1038. View

Noble C, Chen Y, Dong H, Gu F, Pheng Lim S, Schul W . Strategies for development of Dengue virus inhibitors. Antiviral Res. 2010; 85(3):450-62. DOI: 10.1016/j.antiviral.2009.12.011. View

Howe M, Bodoor K, Carlson D, Hughes P, Alwarawrah Y, Loiselle D . Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70. Chem Biol. 2014; 21(12):1648-59. PMC: 4272656. DOI: 10.1016/j.chembiol.2014.10.016. View

Powers M, Clarke P, Workman P . Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis. Cancer Cell. 2008; 14(3):250-62. DOI: 10.1016/j.ccr.2008.08.002. View

McConnell J, McAlpine S . Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorg Med Chem Lett. 2013; 23(7):1923-8. PMC: 3602338. DOI: 10.1016/j.bmcl.2013.02.014. View

Chavez-Salinas S, Ceballos-Olvera I, Reyes-Del Valle J, Medina F, Del Angel R . Heat shock effect upon dengue virus replication into U937 cells. Virus Res. 2008; 138(1-2):111-8. DOI: 10.1016/j.virusres.2008.08.012. View

10.

Cheung R, Dosch H . The growth transformation of human B cells involves superinduction of hsp70 and hsp90. Virology. 1993; 193(2):700-8. DOI: 10.1006/viro.1993.1178. View

11.

Reyes-Del Valle J, Chavez-Salinas S, Medina F, Del Angel R . Heat shock protein 90 and heat shock protein 70 are components of dengue virus receptor complex in human cells. J Virol. 2005; 79(8):4557-67. PMC: 1069525. DOI: 10.1128/JVI.79.8.4557-4567.2005. View

12.

Thomas S, Endy T . Critical issues in dengue vaccine development. Curr Opin Infect Dis. 2011; 24(5):442-50. DOI: 10.1097/QCO.0b013e32834a1b0b. View

13.

Ross T . Dengue virus. Clin Lab Med. 2010; 30(1):149-60. PMC: 7115719. DOI: 10.1016/j.cll.2009.10.007. View

14.

Lai C, Park K, Lee D, Alberobello A, Raffeld M, Pierobon M . HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer. Oncogene. 2013; 33(40):4867-76. PMC: 4002667. DOI: 10.1038/onc.2013.439. View

15.

Jego G, Hazoume A, Seigneuric R, Garrido C . Targeting heat shock proteins in cancer. Cancer Lett. 2010; 332(2):275-85. DOI: 10.1016/j.canlet.2010.10.014. View

16.

Whitehead S, Blaney J, Durbin A, Murphy B . Prospects for a dengue virus vaccine. Nat Rev Microbiol. 2007; 5(7):518-28. DOI: 10.1038/nrmicro1690. View

17.

Powers M, Workman P . Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett. 2007; 581(19):3758-69. DOI: 10.1016/j.febslet.2007.05.040. View

18.

Hughes P, Barrott J, Carlson D, Loiselle D, Speer B, Bodoor K . A highly selective Hsp90 affinity chromatography resin with a cleavable linker. Bioorg Med Chem. 2012; 20(10):3298-305. PMC: 3345094. DOI: 10.1016/j.bmc.2012.03.043. View

19.

Carlson D, Franke A, Weitzel D, Speer B, Hughes P, Hagerty L . Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor. ACS Chem Biol. 2013; 8(12):2715-23. PMC: 4445880. DOI: 10.1021/cb400407c. View

20.

Powers M, Clarke P, Workman P . Death by chaperone: HSP90, HSP70 or both?. Cell Cycle. 2009; 8(4):518-26. DOI: 10.4161/cc.8.4.7583. View