Antiviral activity of nordihydroguaiaretic acid on localisolations ofFortSherman virus (Orthobunyavirus)

MARTINEZ FLORENCIA; AGUILAR JAVIER; CONTIGIANI MARTA; NÚÑEZ MONTOYA SUSANA; KONIGHEIM BRENDA

Jornada; IV Reunión Conjunta de Sociedades de Biología de la República Argentina; 2020

Sociedad Argentina de Biología

The genus Orthobunyavirus (arbovirus) is a group of viruses, which can cause infection in humans and is characterized by its lack of therapeutic treatment or preventive vaccine. We proposed to study the in vitro antiviral activity of nordihydroguaiaretic acid (NDGA), the most important activecompound of Larrea divaricata Cav. (Zygophyllaceae), against two local isolates of the Fort Sherman virus (FSV) as a model for the genus Orthobunyavirus and to evaluate the effect of NDGA as a lipolytic agent in the cell cycle of these viral isolates. The method of reducing plaque forming units in LLC-MK2 cells was used to evaluate the action of NDGA on FSV isolates, CbaAr426 and SFCrEq231, under different conditions. Furthermore, the ability of the NDGA to be incorporated into these cells was quantified by HPLC. NDGA showed antiviral activity with a similar dose-dependent inhibition in both isolates (> 90 I%). The NDGA selectivity index was 4.8 and 4.6 for CbaAr426 and SFCrEq231, respectively. It was established that NDGA has a better inhibition (> 90 I%) 1 h post-infection (p.i.), showing a different behavior on each viral isolate. The effect of NDGA was equally important at 8 hrs p.i. on the CbaAr426 isolation. However, on SFCrEq231, it was active during the first 2 h p.i. The antiviral effect of NDGA has previously been related to its ability to alter lipid metabolism by interfering with the sterol regulatory element-binding protein (SREBP) and 5-lipoxygenase (5-LOX) pathway. Using caffeic acid, an inhibitor of 5-LOX, we determined that the inhibition of this enzyme negatively affected replication in both isolates; and through the use of resveratrol, an inhibitor of SREBP1, it was demonstrated that the negativeregulation of this pathway only had an action on the reduction of SFCrEq231. We estimate that NDGA acts intracellularly since it showed the ability to incorporate in LLC-MK2 cells (15% enters between 0?15 min). The information provided in this work makes NDGA a potential antiviral candidate for Orthobunyavirus infections, especially on FSV isolates circulating in Argentina. On the other hand, the results obtained make new contributions to the biochemical study of FSV, a poorly studied and potentially dangerous infection