Use of ouabain antagonists to inhibit viral infection
Inventors
Collins, Peter • Lingemann, Matthias • Munir, Shirin
Assignees
US Department of Health and Human Services
Publication Number
US-11337988-B2
Publication Date
2022-05-24
Expiration Date
2039-09-26
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Abstract
Embodiments of a method for inhibiting viral infection in a subject are provided herein. In some embodiments, the method comprises administration of a competitive antagonist of ouabain binding to ATP1A1 to inhibit respiratory syncytial virus infection in the subject.
Core Innovation
The invention relates to methods for inhibiting viral infection in a subject by administering a competitive antagonist of ouabain binding to ATPase Sodium/potassium-transporting subunit alpha-1 (ATP1A1), specifically to inhibit respiratory syncytial virus (RSV) infection. The method includes selecting a subject with or at risk of viral infection, particularly negative-sense single-stranded RNA viruses, viruses of the Pneumoviridae family, or viruses utilizing ATP1A1 signaling for cellular entry, and administering a therapeutically effective amount of such an agent, exemplified by PST2238.
The problem addressed is the substantial health impact of viral infections, specifically RSV, which is the leading viral cause of acute pediatric lower respiratory tract infections worldwide, for which no effective vaccine or antiviral drug exists. RSV causes repeated infections with severe lower respiratory tract disease, especially in vulnerable populations such as the elderly and immunocompromised individuals. Despite existing passive immunization strategies, there remains a critical need for therapeutics to treat RSV infection.
The disclosure provides novel methods by demonstrating that ATP1A1 is a host protein involved in RSV cellular entry, mediating a signaling pathway that triggers viral uptake through macropinocytosis. The method uniquely uses competitive antagonists of ouabain binding to ATP1A1 to inhibit viral entry and replication, contrary to prior findings that cardiotonic steroid agonists like ouabain inhibit viral infection. This approach targets the ATP1A1-Src kinase-EGFR signaling pathway essential for RSV infection, offering a new therapeutic target and demonstrating the efficacy of PST2238 as an anti-RSV agent.
Claims Coverage
The patent includes two independent claims directed to methods of inhibiting RSV replication and treating RSV infection by administering PST2238. The main inventive features focus on the use of PST2238, administration routes, and target subjects.
Use of PST2238 to inhibit RSV replication
The method comprises administering a therapeutically effective amount of PST2238 to a subject to inhibit replication of Respiratory Syncytial Virus (RSV), thereby achieving inhibition of RSV replication in the subject.
Administration methods of PST2238 for RSV inhibition and treatment
The PST2238 agent is administered by one or more routes selected from oral, intranasal, inhalation, intramuscular, intravenous, peritoneal, or subcutaneous administration. Specific embodiments include intranasal administration and administration using a nebulizer.
Target subjects for PST2238 administration
The methods target human subjects, including specific subpopulations such as children and individuals over 65 years old, for the inhibition or treatment of RSV infection or replication.
The claims cover methods using PST2238 to inhibit RSV replication and treat RSV infection in subjects, highlighting administration routes and target populations. The core inventive aspect is the therapeutic use of the competitive antagonist PST2238 against RSV infection.
Stated Advantages
Inhibition of RSV infection and replication in the subject.
Ability to administer via multiple routes including potentially non-invasive methods like intranasal delivery or nebulization.
Utility in vulnerable populations such as children and the elderly.
Documented Applications
Inhibiting or treating RSV infection in human subjects, including high risk groups such as infants, elderly, and immunocompromised patients.
Potential treatment or prophylaxis for viral infections caused by viruses of the Pneumoviridae family or negative-sense single-stranded RNA viruses that utilize ATP1A1 signaling.
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