title: Suppressive Effects of the Site 1 Protease (S1P) Inhibitor, PF-429242, on Dengue Virus Propagation.
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.
authors.affiliation: Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. uchidaleo@rakuno.ac.jp.
authors.forename: Leo
authors.initials: L
authors.lastname: Uchida
authors.affiliation: Department of Emerging Infectious Disease, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. shuzourata@nagasaki-u.ac.jp.
authors.forename: Shuzo
authors.initials: S
authors.lastname: Urata
authors.affiliation: Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. ulanday@tm.nagasaki-u.ac.jp.|Graduate school of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. ulanday@tm.nagasaki-u.ac.jp.
authors.forename: Gianne Eduard L
authors.initials: GE
authors.lastname: Ulanday
authors.affiliation: Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. yuki.takamatsu@staff.uni-marburg.de.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takamatsu
authors.affiliation: Department of Emerging Infectious Disease, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. j-yasuda@nagasaki-u.ac.jp.|Leading graduate school program, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. j-yasuda@nagasaki-u.ac.jp.
authors.forename: Jiro
authors.initials: J
authors.lastname: Yasuda
authors.affiliation: Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. moritak@nagasaki-u.ac.jp.|Leading graduate school program, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. moritak@nagasaki-u.ac.jp.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Morita
authors.affiliation: Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. hayasaka@nagasaki-u.ac.jp.|Leading graduate school program, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. hayasaka@nagasaki-u.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hayasaka
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D003715:Dengue / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C570314:PF-429242; D011759:Pyrrolidines; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1
keywords: PF-429242; S1P; SREBPs; antivirus drug; dengue virus