INVESTIGADORES
RAMIREZ Javier Alberto
congresos y reuniones científicas
Título:
Antiviral and immunomodulatory activities of synthetic stigmastane analogs
Autor/es:
FLAVIA M. MICHELINI; JAVIER A. RAMIREZ; ALEJANDRO MOLINARI; MARIO GALIGNANA; LYDIA GALAGOVSKY; LAURA ALCHÉ
Reunión:
Congreso; XLVIII Reunión Anual de Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular; 2012
Resumen:
The stigmastane analog
(22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) displays antiviral activity in vitro
against Herpes Simplex Virus Type 1 (HSV-1). The compound also significantly diminishes
proinflammatory cytokines production in inflammatory cells. The 3-keto group
and the double bond in r4 in the steroid A ring provide the molecule with
structural similarities to that of corticosteroids. In order to improve the
immunomodulatory activity of this molecule, we designed new stigmastane analogs,
keeping the (22S,23S)-22,23-dihydroxylated side chain of the steroidal
structure, responsible of the antiviral activity, and introducing an additional
double bond in r1 and/or a fluorine atom in the molecule, structural
features known to improve the anti-inflammatory activity of steroidal drugs. The
presence of the r1-4 ceto in the stigmastane structure
reduced anti HSV-1 activity and did not improve the immunomodulatory effect of
the compound. However, a fluorine atom in C6 enhanced both antiviral and immunosuppressive
activities of the new compounds, since they were more effective than compound 1 to reduce virus yields in epithelial
cells infected with HSV-1 and cytokine production in inflammatory cells, as
determined by virus yield reduction assays and ELISA, respectively. Radioligand
binding assays and reporter gene induction assays showed that the stigmastane
analogs did not exhibit affinity for the glucocorticoids and mineralocorticoid
receptors. The compounds would be exerting their effect through a mechanism of
action different from that of commercial anti-inflammatory steroidal drugs.