Uchida Leo, Urata Shuzo, Ulanday Gianne Eduard L, Takamatsu Yuki, Yasuda Jiro, Morita Kouichi, Hayasaka Daisuke
Department of Virology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
Department of Emerging Infectious Disease, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
Viruses. 2016 Feb 10;8(2):46. doi: 10.3390/v8020046.
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.
登革病毒（DENV）感染引发了全球最广泛传播的蚊媒疾病之一。尽管需求迫切，但有效的疫苗和实用的抗病毒疗法仍在研发中。细胞内脂质水平由固醇调节元件结合蛋白（SREBPs）调控，SREBPs由丝氨酸蛋白酶即1号位点蛋白酶（S1P）激活。小分子化合物PF - 429242是一种已知的S1P抑制剂，其抗病毒作用已在一些病毒中得到报道。在本研究中，我们使用几种灵长类动物来源的细胞系，检测了PF - 429242对所有四种血清型登革病毒的抗病毒效果。此外，通过用该药物连续传代评估了耐药登革病毒突变体的出现情况。还通过添加细胞外脂质评估了登革病毒感染期间对细胞内脂质的依赖性。添加PF - 429242显示出对所有登革病毒血清型病毒增殖的抑制作用。我们发现，经PF - 429242处理连续传代五次后，不太可能出现耐药登革病毒突变体。尽管PF - 429242降低了细胞内胆固醇和脂滴的水平，但添加外源性胆固醇或脂肪酸并不能恢复病毒增殖，这表明PF - 429242处理导致的脂滴和胆固醇减少与其抗登革病毒增殖的作用机制无关。我们的结果表明，PF - 429242是一种有前景的抗登革病毒药物候选物。
