Laboratory of Virology, Department of Biological Chemistry, IQUIBICEN, School of Science, University of Buenos Aires, Argentina.
Bioorg Med Chem. 2013 Jan 15;21(2):560-8. doi: 10.1016/j.bmc.2012.10.054. Epub 2012 Nov 15.
Many viral infections are associated with the development of immunopathologies and autoimmune diseases, which are of difficult treatment and for which no vaccines are yet available. Obtaining compounds that conjugate both antiviral and immunomodulatory activities in the same molecule would be very useful for the prevention and/or treatment of these immunopathologies. The compound (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) displays anti-Herpes simplex virus type 1 activity in vitro and reduces the incidence of herpetic stromal keratitis (HSK) in mice, a chronic inflammatory syndrome induced by ocular HSV-1 infection. In the present study, compound 1 showed opposite immunomodulatory properties in vitro. It induced the release of pro-inflammatory cytokines in HSV-1-infected epithelial cells of ocular origin, and significantly reduced the production of these cytokines in LPS-activated macrophages. RNA microarrays revealed various overexpressed and repressed genes in compound 1 treated infected epithelial cells and activated macrophages, many of which are associated with innate immune responses and inflammatory processes. These immunomodulatory properties of compound 1, together with its previously reported antiviral activity, make it a potential drug for the treatment of HSK and many other immunopathologies of viral and non-viral origin.
许多病毒感染与免疫病理学和自身免疫性疾病的发展有关，这些疾病难以治疗，目前尚无疫苗可用。获得既能抗病毒又能具有免疫调节活性的化合物对于预防和/或治疗这些免疫病理学将非常有用。化合物（22S，23S）-22,23-二羟基豆甾-4-烯-3-酮（化合物 1）在体外具有抗单纯疱疹病毒 1 活性，并降低小鼠单纯疱疹病毒 1 感染引起的慢性炎症综合征——疱疹性基质角膜炎（HSK）的发病率。在本研究中，化合物 1 在体外表现出相反的免疫调节特性。它在 HSV-1 感染的眼源上皮细胞中诱导促炎细胞因子的释放，并显著降低 LPS 激活的巨噬细胞中这些细胞因子的产生。RNA 微阵列揭示了在化合物 1 处理的感染上皮细胞和激活的巨噬细胞中表达上调和下调的各种基因，其中许多与先天免疫反应和炎症过程有关。化合物 1 的这些免疫调节特性，加上其先前报道的抗病毒活性，使其成为治疗 HSK 和许多其他病毒和非病毒来源的免疫病理学的潜在药物。
