Pharmaceutical compositions with antiflaviviral activity
Inventors
Li, Hongmin • Kramer, Laura D. • Li, Zhong • Huang, Ruili • Xia, Menghang
Assignees
Health Research Inc • US Department of Health and Human Services
Publication Number
US-11491123-B2
Publication Date
2022-11-08
Expiration Date
2037-06-23
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Abstract
Provided is a method of inhibiting viral replication, including contacting one or more cells that has been infected or contacted with a flavivirus with an effective amount of niclosamide, temoporfin, nitazoxanide, tizoxanide, erythrosin B, methylene blue. Contacting one or more cells that have been infected with a flavivirus may include administering the compound to a mammal, a human, or other subject. The flavivirus may be Dengue virus serotype 1, Dengue virus serotype 2, Dengue virus serotype 3, Dengue virus serotype 4, yellow fever virus, West Nile virus, Zika virus, Japanese encephalitis virus, tick-born encephalitis virus, Powassan virus, St. Louis encephalitis virus, or other flavivirus.
Core Innovation
The invention relates to compositions and methods for inhibiting replication of flaviviruses, including treatment and prevention of flaviviral infections in subjects such as mammals and humans. Specifically, the disclosure provides methods of contacting cells infected with flaviviruses, including administration of compounds such as niclosamide, temoporfin, nitazoxanide, tizoxanide, erythrosin B, and methylene blue, or their pharmaceutically acceptable salts, to inhibit viral replication.
The problem addressed involves the lack of safe and effective vaccines and pharmacological treatments for many flaviviruses, including Dengue virus serotypes 1 to 4, Zika virus, West Nile virus, Japanese encephalitis virus, and others. The invention aims to provide antiviral therapeutics that can be administered to infected individuals who may not have received vaccinations or in cases where vaccination is difficult or dangerous.
Claims Coverage
The patent contains three independent claims focusing on methods of inhibiting viral replication by contacting infected cells or administering compounds to subjects.
Method of inhibiting viral replication by contacting infected cells with specified compounds
A method comprising contacting one or more cells infected with a flavivirus with an effective amount of a compound selected from niclosamide, temoporfin, nitazoxanide, tizoxanide, erythrosine B, methylene blue, pharmaceutically acceptable salts thereof, and combinations thereof.
Method of inhibiting viral replication by administering compounds to subjects
A method comprising administering to a subject, such as a mammal or human, an effective amount of a compound selected from the group consisting of niclosamide, temoporfin, nitazoxanide, tizoxanide, erythrosine B, methylene blue, their pharmaceutically acceptable salts, and combinations thereof, to inhibit replication of a flavivirus including Dengue virus serotypes, yellow fever, West Nile, Zika, and Japanese encephalitis viruses.
Method of inhibiting viral replication using specific compounds targeting Zika virus
A method of inhibiting viral replication by contacting or administering one or more cells infected with Zika virus with effective amounts of compounds selected from niclosamide, temoporfin, nitazoxanide, tizoxanide, erythrosine B, methylene blue, pharmaceutically acceptable salts thereof, and combinations of two or more thereof.
The claims cover methods of inhibiting flavivirus replication by contacting infected cells or administering compounds that orthosterically inhibit NS2B-NS3 protease interaction, including specific therapeutics targeting various flaviviruses, especially Zika virus, with the selected compounds and pharmaceutically acceptable salts.
Stated Advantages
Compounds identified have low nanomolar efficacy and high therapeutic indices, indicating potent antiflaviviral activity with low cytotoxicity.
The methods provide broad-spectrum antiviral activity against multiple flaviviruses including Dengue virus, Zika virus, West Nile virus, and others.
Certain compounds such as temoporfin and methylene blue inhibit viral replication effectively without the need for photoactivation.
The methods allow for administration at different stages of infection, including late stages, showing effectiveness for both prevention and treatment.
Identified compounds have potential for repurposing due to existing clinical approval for other medical uses, indicating suitability for rapid clinical application.
Documented Applications
Treatment of subjects infected with flaviviruses including Dengue virus serotypes 1 to 4, yellow fever virus, West Nile virus, Zika virus, Japanese encephalitis virus, tick-borne encephalitis virus, Powassan virus, and St. Louis encephalitis virus.
Prevention of flavivirus infection in subjects suspected of exposure or at risk, by administering effective amounts of the disclosed compounds.
Inhibition of flaviviral replication in cells infected with flaviviruses either in vivo or ex vivo, including human placental epithelial cells and induced pluripotent stem cell-derived human neural progenitor cells relevant to Zika virus infection.
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