IQUIBICEN   23947
INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CIENCIAS EXACTAS Y NATURALES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Anti-HSV-1 synthetic azasteroids display immunomodulating properties
Autor/es:
DÁVOLA, M.E.; RAMÍREZ, J.A.; ALCHÉ, L.E.; BARQUERO, A.A.
Lugar:
London, Ontario
Reunión:
Congreso; 34th Annual Meeting of the American Society for Virology; 2015
Institución organizadora:
American Society for Virology
Resumen:
Herpes simplex virus type 1 (HSV-1)-induced disease occurs as a result of a primary infection in the epithelium and then, cells like macrophages intervene in clearing the virus from the infected area and in the development of the immunopathological reaction. HSV-1 induces a strong NF-κB nuclear translocation in different cell lines that could have several functions: to promote viral replication and mediate the cytokine production. For the treatment of this immunopathology, we have proposed to obtain compounds that conjugate both antiviral and immunomodulatory activities in the same molecule. Recently, we have synthesized azasteroids with different diamide side chains; in particular, U20-12 (N-((tert-butylcarbamoyl)methyl)-N-(4-fluorophenyl)-3bhydroxyandrost-5-ene-17b-carboxamide) and U16-L3H (N-((tert-butylcarbamoyl)methyl)-N-(4-chlorophenyl)-3β-hydroxy-20-oxo-pregn-5-ene-16α-carboxamide) have interesting antiherpetic activity in vitro. In order to evaluate their potential as future drugs, we explored the immunomodulatory properties of both sterol analogues. Therefore, we investigated their effect on NF- κB activation and cytokine secretion induced by viral (HSV-1) and non-viral (LPS or TNF-α) stimuli, in epithelial cells (A549) and macrophages (J774.A1) using indirect immunofluorescence (IFI) assay and ELISA, respectively. First, we observed that neither U20-12 nor U16-L3H affected the NF-κB nuclear translocation in A549 and J774.A1 cells infected with HSV-1 (moi = 10). Besides, none of them restrained NF-κB translocation in TNF-α-induced epithelial cells and in LPS-stimulated macrophages.Then, we found that U16-L3H significantly increased the production of IL-8 and IL-6 in comparison with untreated-A549 cells, whereas U20-12 did not affect the synthesis of either cytokine. In contrast, both compounds significantly reduced the secretion of IL-6 and TNF-α in comparison with untreated-J744.A1 cells. Also, when compounds were added to HSV-1 or LPS stimulated J774.A1, both compounds significantly reduced the production of IL-6 and TNF-α in comparison with stimulated-J744.A1 cells.These interesting immunomodulatory properties of U20-12 and U16-L3H, together with their previously reported antiviral activity, make them potential drugs for the treatment of HSV-1.