First report of antiviral activity of nordihydroguaiaretic acid against Fort Sherman virus (Orthobunyavirus)

MARTINEZ F.; MUGAS M.L.; AGUILAR J.J.; MARIONI J.; CONTIGIANI M.S.; NÚÑEZ MONTOYA S.C.; KONIGHEIM B.

ANTIVIRAL RESEARCH

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2020

0166-3542

The genus Orthobunyavirus are a group of viruses within arbovirus, with a zoonoticcycle, some of which could lead to human infection. A characteristic of these viruses istheir lack of antiviral treatment or vaccine for its prevention. The objective of this workwas to study the in vitro antiviral activity of nordihydroguaiaretic acid (NDGA), themost important active compound of Larrea divaricata Cav. ( Zigophyllaceae ),against Fort Sherman virus (FSV) as a model of Orthobunyavirus genus. At the sametime, the effect of NDGA as a lipolytic agent on the cell cycle of this viral model wasassessed. The method of reducing plaque forming units on LLC-MK2 cells was used todetect the action of NDGA on CbaAr426 and SFCrEq231 isolates of FSV. NDGA didnot show virucidal effect, but it had antiviral activity with a similar inhibition in bothisolates, which was dose dependent. It was established that the NDGA has a betterinhibition one-hour post-internalization (p.i.), showing a different behavior in eachisolate, which was dependent upon the time p.i. Since virus multiplication is dependenton host cell lipid metabolism, the antiviral effect of NDGA has been previously relatedto its ability to disturb the lipid metabolism, probably by interfering with the 5-lipoxigenase (5‑LOX) and the sterol regulatory element-binding proteins (SREBP)pathway. We determined by using caffeic acid, a 5‑LOX inhibitor, that the inhibition ofthis enzyme negatively affected the FSV replication; and by means of resveratrol, aSREBP1 inhibitor, it was showed that the negative regulation of this pathway only hadaction on the SFCrEq231 reduction. In addition, it was proved that the NDGA actsintracellularly, since it showed the ability to incorporate into LLC‑MK2 cells. Theinformation provided in this work converts the NDGA into a compound with antiviralactivity in vitro against FSV (Orthobunyavirus), which can be subjected to structuralmodifications in the future to improve the activity.