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Viruses 2016, 8(2), 46; doi:10.3390/v8020046

Suppressive Effects of the Site 1 Protease (S1P) Inhibitor, PF-429242, on Dengue Virus Propagation

1
Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
2
Department of Emerging Infectious Disease, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
3
Graduate school of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
4
Leading graduate school program, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
*
Author to whom correspondence should be addressed.
Received: 18 November 2015 / Revised: 24 January 2016 / Accepted: 4 February 2016 / Published: 10 February 2016
(This article belongs to the Section Antivirals & Vaccines)
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Abstract

Dengue virus (DENV) infection causes one of the most widespread mosquito-borne diseases in the world. Despite the great need, effective vaccines and practical antiviral therapies are still under development. Intracellular lipid levels are regulated by sterol regulatory elements-binding proteins (SREBPs), which are activated by serine protease, site 1 protease (S1P). Small compound PF-429242 is known as a S1P inhibitor and the antivirus effects have been reported in some viruses. In this study, we examined the anti-DENV effects of PF-429242 using all four serotypes of DENV by several primate-derived cell lines. Moreover, emergence of drug-resistant DENV mutants was assessed by sequential passages with the drug. DENV dependency on intracellular lipids during their infection was also evaluated by adding extracellular lipids. The addition of PF-429242 showed suppression of viral propagation in all DENV serotypes. We showed that drug-resistant DENV mutants are unlikely to emerge after five times sequential passages through treatment with PF-429242. Although the levels of intracellular cholesterol and lipid droplets were reduced by PF-429242, viral propagations were not recovered by addition of exogenous cholesterol or fatty acids, indicating that the reduction of LD and cholesterol caused by PF-429242 treatment is not related to its mechanism of action against DENV propagation. Our results suggest that PF-429242 is a promising candidate for an anti-DENV agent. View Full-Text
Keywords: dengue virus; antivirus drug; PF-429242; SREBPs; S1P dengue virus; antivirus drug; PF-429242; SREBPs; S1P
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MDPI and ACS Style

Uchida, L.; Urata, S.; Ulanday, G.E.L.; Takamatsu, Y.; Yasuda, J.; Morita, K.; Hayasaka, D. Suppressive Effects of the Site 1 Protease (S1P) Inhibitor, PF-429242, on Dengue Virus Propagation. Viruses 2016, 8, 46.

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