Selective Estrogen Receptor Modulators Limit Alphavirus Infection by Targeting the Viral Capping Enzyme nsP1

Abstract

Alphaviruses cause animal or human diseases that are characterized by febrile illness, debilitating arthralgia, or encephalitis. Selective estrogen receptor modulators (SERMs), a class of FDA-approved drugs, have been shown to possess antiviral activities against multiple viruses, including Hepatitis C virus, Ebola virus, dengue virus, and vesicular stomatitis virus. Here, we evaluated three SERM compounds, namely 4-hydroxytamoxifen, tamoxifen, and clomifene, for plausible antiviral properties against two medically important alphaviruses, chikungunya virus (CHIKV) and Sindbis virus (SINV). In cell culture settings, these SERMs displayed potent activity against CHIKV and SINV at non-toxic concentrations with EC 50 values ranging between 400 nM and 3.9 μM. Further studies indicated that these compounds inhibit a post-entry step of the alphavirus life cycle, while enzymatic assays involving purified recombinant proteins confirmed that these SERMs target the enzymatic activity of non-structural protein 1 (nsP1), the capping enzyme of alphaviruses. Finally, tamoxifen treatment restrained CHIKV growth in the infected mice and diminished musculoskeletal pathologies. Combining biochemical, cell culture-based studies, and in vivo analyses, we strongly argue that SERM compounds, or their derivatives, may provide for attractive therapeutic options against alphaviruses.

Seroprevalence and biochemical parameters among patients with Chikungunya in Adamaoua region, Cameroon: A cross‐sectional study

“…Even if the reasons for this exposure are still poorly understood, some authors indicate that estradiol, produced by women, would increase their tendency to produce antibodies more than men [28]. Furthermore, other sources reveal that estrogen receptor modulators have the same protective effect against alphaviruses by acting as replication inhibitors [29].…”

SAM-dependent viral MTase inhibitors: herbacetin and caffeic acid phenethyl ester, structural insights into dengue MTase

“…After incubation reaction stopped by adding acetonitrile in 1 : 2 (vol/vol). 1mM caffeine was used as internal control [22], [54]. The mixture was vortex-mixed for 15 s, and protein was precipitated for 20 min at 18,500 g. Supernatant was transferred to sample vials for CE analysis performed as mentioned in Mudgal et.…”

Activity profiling of deubiquitinating inhibitors-bound to SARS-CoV-2 papain like protease with antiviral efficacy in murine infection model

“…To determine the cytotoxic profiles of identified compounds on Vero cells, MTT assay was performed as described previously [53]. Briefly, Vero cells were seeded onto wells of 96-well cell-culture plate at a density of 1 × 10 4 cells/well and the plates were incubated at 37 °C and 5% CO 2 overnight for proper adherence of cells.…”