Compounds and methods for treatment and prevention of Flavivirus infection
Inventors
Tang, Hengli • Lee, Emily M. • Cheng, Yichen • Zhou, Yi • Zheng, Wei • Huang, Ruili • Xu, Miao • HUANG, Wenwei • Xia, Menghang • Song, Hongjun • Ming, Guo-li • WEN, ZHEXING
Assignees
Florida State University Research Foundation Inc • Johns Hopkins University • US Department of Health and Human Services
Publication Number
US-10940188-B2
Publication Date
2021-03-09
Expiration Date
2037-07-14
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Abstract
The present invention concerns the use of compounds for the treatment or prevention of Flavivirus infections, such as Zika virus infections. Aspects of the invention include methods for treating or preventing Flavivirus virus infection, such as Zika virus infection, by administering a compound or class of compound disclosed herein, such as a niclosamide compound, an emricasan compound, a cyclin-dependent kinase inhibitor, a proteasome inhibitor, or a combination of two or more of the foregoing, to a subject in need thereof; methods for inhibiting Flavivirus infections such as Zika virus infections in a cell in vitro or in vivo; pharmaceutical compositions; packaged dosage formulations; and kits for treating or preventing Flavivirus infections, such Zika virus infections.
Core Innovation
The invention relates to the use of compounds, including niclosamide compounds, emricasan compounds, cyclin-dependent kinase (CDK) inhibitors, proteasome inhibitors, and other specified compounds or combinations thereof, for the treatment or prevention of Flavivirus infections, with an emphasis on Zika virus infection. Methods include administering these compounds to subjects in need for inhibiting Flavivirus infection or suppressing Flavivirus-induced caspase-3 activity, as well as pharmaceutical compositions, packaged dosage formulations, and kits for such treatments or prevention.
The problem being addressed is the global public health challenge posed by Zika virus, a mosquito-borne flavivirus which has re-emerged and spread across multiple countries. Approximately 20% of infected individuals develop symptoms, similar to other arboviruses, but uniquely Zika virus causes congenital defects such as microcephaly and is associated with Guillain-Barré syndrome in adults. There is a lack of available drugs or vaccines to treat or prevent Zika virus and other Flavivirus infections, demanding the discovery of effective therapeutic compounds.
The inventors identified through large scale compound screening that certain compounds inhibit Zika virus infection or suppress infection-induced caspase-3 activity, reducing cell death in human neural cells including neural progenitor cells and astrocytes. Emricasan, a pan-caspase inhibitor, protects infected cells by suppressing caspase-3 activity without reducing viral replication. Several CDK inhibitors, including PHA-690509 and structurally unrelated compounds, inhibit Zika virus replication in a dose-dependent manner and are effective when applied before or after viral exposure. Niclosamide, an FDA-approved anthelmintic, inhibits viral replication at sub-micromolar concentration. Combinations of these compounds show synergistic protective effects against virus-induced neural cell death.
Claims Coverage
The patent contains a set of independent claims focusing primarily on therapeutic methods involving administration of emetine or its pharmaceutically acceptable salts for the treatment or prevention of Zika virus infection, and methods of inhibiting Zika virus infection in vitro or in vivo.
Use of emetine compounds for treating or preventing Zika virus infection
Administering an effective amount of emetine, or a pharmaceutically acceptable salt thereof, to a subject in need for treating or preventing Zika virus infection.
Therapeutic administration of emetine to infected subjects
Administering emetine or its pharmaceutically acceptable salt as therapy to subjects confirmed to have Zika virus infection.
Identification of infected subjects prior to emetine administration
Performing assays such as RT-PCR, immunological assays, or plaque-reduction neutralization testing (PRNT) on biological samples to identify Zika virus infection before administration of emetine.
Prophylactic use of emetine in uninfected subjects
Administering emetine or its pharmaceutically acceptable salt to subjects not yet infected with Zika virus as a prophylactic measure.
Diverse routes of administration for emetine
Administering emetine via oral, nasal, rectal, parenteral, subcutaneous, intramuscular or intravascular (e.g., intravenous) routes.
Combination therapies including emetine
Administering emetine in the same or separate formulation along with additional agents to treat or prevent Zika virus infection or associated symptoms.
Compositions comprising emetine and pharmaceutically acceptable carriers
Formulating emetine with pharmaceutically acceptable buffers, carriers, or diluents for administration.
Methods for inhibiting Zika virus infection in cells with emetine
Contacting human or non-human animal cells in vitro or in vivo with emetine or its pharmaceutically acceptable salt before or after exposure to Zika virus to inhibit infection.
The independent claims cover therapeutic and prophylactic administration of emetine compounds for Zika virus infection using various administration routes and compositions, including methods of identifying infected subjects and combination therapies, as well as methods of inhibiting viral infection in cells in vitro or in vivo using emetine.
Stated Advantages
Identification of compounds that either protect neural cells from virus-induced death or suppress Zika virus replication, providing candidates for anti-Zika drug development.
Synergistic effect observed in combinations of compounds (e.g., Emricasan and CDK inhibitors) that improve protection of human neural cells from ZIKV-induced cell death.
Niclosamide is an FDA-approved category B drug with broad antiviral properties and effective at submicromolar concentrations against ZIKV, representing a promising candidate with a favorable safety profile.
Pharmacological CDK inhibitors with diverse structures inhibit ZIKV replication, providing multiple chemical scaffolds for medicinal chemistry optimization.
The caspase-3 activity assay is a robust screening method suitable for large-scale high-throughput compound screening for ZIKV infection interventions.
Documented Applications
Treatment and prevention of Flavivirus infections, especially Zika virus infection, in human and non-human animal subjects.
Inhibition of Flavivirus infection in human or non-human animal cells in vitro or in vivo, including neural progenitor cells and astrocytes.
Use of pharmaceutical compositions, packaged dosage formulations, and kits containing compounds such as niclosamide, emricasan, CDK inhibitors, proteasome inhibitors, or combinations thereof for treating or preventing Flavivirus infections.
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