Selective Estrogen Receptor Modulators Limit Alphavirus Infection by Targeting the Viral Capping Enzyme nsP1
| Autor: | Shweta Choudhary, Chandrima Bharadwaj, Aakriti Dubey, Soumen Basak, Shailly Tomar, Perumal Nagarajan, Yashika Ratra, Rajat Mudgal, Megha Aggarwal |
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| Rok vydání: | 2022 |
| Předmět: |
Selective Estrogen Receptor Modulators
Sindbis virus Hepatitis C virus viruses Alphavirus Dengue virus Viral Nonstructural Proteins medicine.disease_cause Virus Replication Antiviral Agents Virus Cell Line Mice medicine Animals Pharmacology (medical) Alphavirus infection Pharmacology Ebola virus biology Alphavirus Infections virus diseases biology.organism_classification medicine.disease Virology Infectious Diseases Vesicular stomatitis virus Chikungunya virus hormones hormone substitutes and hormone antagonists |
| Zdroj: | Antimicrob Agents Chemother |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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