RT Journal Article
SR Electronic
T1 Selective estrogen receptor modulators limit alphavirus infection by targeting the viral capping enzyme nsP1
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.19.457046
DO 10.1101/2021.08.19.457046
A1 Rajat Mudgal
A1 Chandrima Bharadwaj
A1 Aakriti Dubey
A1 Shweta Choudhary
A1 Perumal Nagarajan
A1 Megha Aggarwal
A1 Yashika Ratra
A1 Soumen Basak
A1 Shailly Tomar
YR 2022
UL http://biorxiv.org/content/early/2022/01/12/2021.08.19.457046.abstract
AB 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 EC50 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.Competing Interest StatementThe authors have declared no competing interest.