WO2021207141A1

WO2021207141A1 - METHODS OF USING NEUROKININ-1 RECEPTOR (NK-1R) ANTAGONISTS TO TREAT β-CORONAVIRUS INFECTION INCLUDING SARS-COV-2 INFECTION AND/OR COVID-19 DISEASE

Info

Publication number: WO2021207141A1
Application number: PCT/US2021/025897
Authority: WO
Inventors: Maria A. NAGEL; Andrew N. BUBAK; Diego Restrepo
Original assignee: The Regents Of The University Of Colorado, A Body Corporate
Priority date: 2020-04-06
Filing date: 2021-04-06
Publication date: 2021-10-14

Abstract

Provided herein are methods for using NK-1R antagonists to treat SARS-CoV-2 infection and/or COVID-19 disease, SARS, MERS-CoV, and other β-coronaviruses.

Description

METHODS OF USING NEUROKININ-1 RECEPTOR (NK-1R) ANTAGONISTS TO TREAT b-CORONA VIRUS INFECTION INCLUDING SARS-COV-2 INFECTION AND/OR COVID-19

DISEASE

GOVERNMENTAL SUPPORT

[001] This invention was made with government support under grant number AG032958 awarded by the National Institutes of Health. The government has certain rights in the invention.

CROSS-REFERENCE TO RELATED APPLICATION [002] This application claims the benefit of U.S. Provisional Application No. 63/005,994, entitled “Methods of Using Neurokinin- 1 Receptor (NK-1R) Antagonists to Treat b- Coronavirus Infection Including SARS-CoV-2 Infection and/or COVID-19 Disease,” filed April 6, 2020, the disclosure of which is incorporated herein by reference in its entirety.

SEQUENCE LISTING

[003] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on April 5, 2021, is named 517709-CU5331H-PCT-SL.txt and is 1299 bytes in size.

FIELD

[004] The present disclosure provides methods for using NK-1 receptor antagonists to treat SARS-CoV-2 infection, COVID-19 disease, SARS, MERS-CoV, and/or other b- coronavirus infection. The disclosure therefore relates to the fields of biology, molecular biology, chemistry, particularly medicinal chemistry, and medicine, and particularly the prevention and treatment of viral disease.

BACKGROUND

[005] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes serious respiratory illness and can lead to coronavirus disease 2019 (COVID-19). Within a short period of the first report of SARS-CoV-2 in 2019, it had spread worldwide, reaching a pandemic level in mere months. The resulting COVID-19 disease has triggered a large number of human casualties. Likewise, severe acute respiratory syndrome coronavirus (SARS) is a viral respiratory disease that was first reported in Asia in February 2003 and quickly spread to about two dozen countries, and Middle East respiratory syndrome coronavirus (MERS) is a viral respiratory disease that was first reported in Saudi Arabia in 2012 and has since spread to more than 27 other countries. There is no specific medicine to prevent or treat COVID-19, SARS, or MERS-CoV, or any other b-coronavirus infection, accordingly, there is an urgent need for the identification and/or development of such therapeutics to limit spread and treat the infected.

[006] The NK-1 receptor (NK-1R) is a neuropeptide receptor which is expressed throughout many tissues, including those in the central and peripheral nervous system. It is involved in the interaction between the nervous and immune systems, via roles in neuroinflammation, neuronal excitation, cell survival, and cell migration. Its broad expression and biological functions have led to interest in, and the development of, multiple NK-1R antagonist compounds. These compounds have been used clinically for the prevention of chemotherapy-induced nausea and vomiting.

SUMMARY

[007] Described herein are methods for using NK-1R antagonists to treat b-coronavirus infection including SARS-CoV-2 infection and/or COVID-19 disease and the related pathogen-induced immunosuppression. Also described herein are compositions for treating b-coronavirus infection including SARS-CoV-2 infection and/or COVID-19 disease. The methods can be used to slow or minimize disease spread, onset or progression.

[008] In certain embodiments, the method includes treating SARS-CoV-2 infection or COVID-19 disease or preventing or minimizing onset or progression of COVID-19 disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an NK-1R antagonist. In some embodiments, the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, or a combination thereof. In some embodiments, the treatment reduces the onset or progression of COVID-19 disease in the subject. In some embodiments, the therapeutically effective amount of the NK-1R antagonist administered to the subject is 20 mg/day to 375 mg/day. In some embodiments, the NK-1R antagonist is administered to the subject orally. In some embodiments, the treatment reduces the onset or progression of COVID-19 disease in the subject and/or provides the subject with protection against SARS-CoV-2. In other embodiments, the treatment decreases susceptibility or inhibits SARS-CoV-2 infection in the subject. In some embodiments, the NK-1R antagonist is administered prior to, concurrently with, or following infection of the subject with a pathogen, exposure to or contact of the subject with a pathogen, or following development of a symptom or pathology of acute or chronic pathogen infection. In some embodiments, the pathogen-induced immunosuppression is caused by SARS-CoV-2.

[009] In certain embodiments, the composition comprises an NK-1R antagonist for use in a method for treating SARS-CoV-2, COVID-19 disease, SARS, MERS-CoV, and other b- coronaviruses and/or pathogen-induced immunosuppression. In some embodiments, the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, or a combination thereof. In certain embodiments, the composition comprises a TRPM5 antagonist for use in a method for treating SARS-CoV-2, COVID-19 disease, SARS, MERS-CoV, other b-coronavirus infection, and/or pathogen-induced immunosuppression.

[0010] In certain embodiments, the method includes treating a b-coronavirus infection and/or related disease, or preventing or minimizing onset or progression of b-coronavirus related disease in a subject, the method comprising administering to the subject a therapeutically effective amount of an NK-1R antagonist. In some embodiments, the b- coronavirus is SARS-CoV-2, SARS, or MERS-CoV. In some embodiments, the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L- 733,060 (Merck), orvepitant, serlopitant, vofopitant, or a combination thereof. In some embodiments, the method inhibits the onset or progression of disease in the subject. In some embodiments, the therapeutically effective amount of the NK-1R antagonist administered to the subject is 20 mg/day to 375 mg/day. In some embodiments, the NK-1R antagonist is administered to the subject orally. In some embodiments, the method reduces the onset or progression of disease in the subject and/or provides the subject with protection against b-coronavirus infection or pathogenesis. In some embodiments, the treatment decreases susceptibility to, or inhibits, b-coronavirus infection in the subject. In some embodiments, the NK-1R antagonist is administered prior to, concurrently with, or following infection of the subject with b-coronavirus, exposure to or contact of the subject with a b-coronavirus infection, or following development of a symptom or pathology of acute or chronic b-coronavirus infection. [0011] In certain embodiments, the composition comprising an NK-1R antagonist for use in a method for treating SARS-CoV-2, COVID-19 disease, SARS, MERS-CoV, and other b-coronaviruses and/or pathogen-induced immunosuppression. In some embodiments, composition of claim 21, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant, or a combination thereof.

[0012] These and other applications of the compositions and methods of the disclosure will be readily apparent to those of skill in the art in view of the following detailed description of various aspects and embodiments of the disclosure and its discovery and practice.

BRIEF DESCRIPTION OF THE DRAWINGS [0013] The following drawings form part of the present specification and are included to further demonstrate certain embodiments of the present disclosure. Certain embodiments can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. The patent or application file contains at least one drawing executed in color.

[0014] FIGURE 1A and IB depict the Sequence Homology of Substance P and Viral Peptides. Asterisks indicate a conserved amino acid substitution relative to the active site sequence for Substance P.

[0015] FIGURE 2 is an immunohistochemical image depicting viral peptide binding to NK-1R in a VZV-infected adult primary human astrocyte.

[0016] FIGURE 3 is a micrograph depicting cytokine production in Naive microglia pretreated with vehicle or NK-1R antagonist (aprepitant) after exposure to exosomes derived from either mock-infected astrocytes or VZV-infected astrocytes. Naive cells were pre-treated with Aprepitant (NK-1R antagonist) and subsequently exposed to exosomes from mock- or VZV-infected cells. Cells exposed to VZV exosomes and vehicle (dark gray bars) were not able to mount an immune response (IFNy or IL-Ib). Conversely, cells exposed to VZV exosomes and Aprepitant (black bars) were able to mount a robust immune response (IFNy and IL-Ib). Cells exposed to mock exosomes and Aprepitant (light gray bars) had no aberrant immune response indicating that the presence of viral peptides are essential for eliciting an immune response. DETAILED DESCRIPTION

[0017] In the following sections, various compositions and methods are described in order to detail various embodiments. Practicing the various embodiments does not require the employment of all of the specific details outlined herein, but rather concentrations, times, and other specific details may be modified. In some cases, well known methods or components have not been included in the description.

[0018] As used herein, "treat" in reference to a disease or condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, and/or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

[0019] As used herein, "therapeutically effective amount" in reference to an agent or compound means an amount of the agent or compound sufficient to treat the subject’s condition or disease but low enough to avoid serious side effects at a reasonable benefit/risk ratio within the scope of sound medical judgment. The safe and effective amount of an agent will vary with the particular agent chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be determined by the skilled artisan.

[0020] For any compound, agent, or composition, the therapeutically effective amount can be estimated initially either in cell culture assays, or in animal models, usually rats, mice, rabbits, dogs, monkeys, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration· [0021] A “subject” or “patient” means any individual having, having symptoms of, or at risk for developing SARS-CoV-2 infection, COVID-19 disease, SARS, MERS-CoV, and other b-coronavirus infections. A subject may be human or non-human, and may include, for example, animals or species used as “model systems” for research purposes, such as a monkey model. In certain embodiments, the subject is a human patient diagnosed with SARS-CoV-2 infection, COVID-19 disease, SARS, MERS-CoV, and/or other b- coronaviruses.

[0022] As used herein, a “pharmaceutical composition” is a formulation containing a compound or agent (e.g., NK-1R antagonist) in a form suitable for administration to a subject. Compounds and agents disclosed herein each can be formulated individually or in any combination into one or more pharmaceutical compositions. Accordingly, one or more administration routes can be properly elected based on the dosage form of each pharmaceutical composition. Alternatively, a compound or agent disclosed herein and one or more additional therapeutic agents can be formulated as a single pharmaceutical composition.

[0023] Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

NK-1R

[0024] The neurokinin 1 receptor (NK-1R) is a neuropeptide receptor that binds tachykinins. The term “NK-1 receptor” or “NK-1R” is used herein as commonly understood in the art to refer to the mammalian receptor also referred to as the tachykinin NK-1 receptor. There are two isoforms of NK-1 R, the full-length (407 amino acid protein) and the truncated (311 amino acid protein), are members of family 1 (rhodopsin-like) of the G protein-coupled receptors, and conservative variants thereof. The NK-1R is a member of the G-protein coupled receptor family and is known to induce the activation of phospholipase C, producing inositol triphosphate. The NK-1R is found throughout the human body, including the central and peripheral nervous systems, and specifically in neurons, brainstem, vascular endothelial cells, muscle, gastrointestinal tracts, genitourinary tract, pulmonary tissue, thyroid gland and various types of immune cells. It is involved in the interaction between the nervous and immune systems, via roles in neuroinflammation, neuronal excitation, cell survival, and cell migration. [0025] The broad expression pattern of and relevant biological functions related to the NK- 1R have led to interest in, and the development of, multiple NK-1R antagonist compounds. These NK-1R antagonists are clinically efficacious because they are selective and potent. As used herein, the term “NK-1 receptor antagonist” or “NK-1R antagonist” refers to a member of the class of compounds that selectively bind to the NK-1R and reduce or eliminate the biological activity thereof, wherein selectively binding refers to about a 100- fold to 10,000-fold higher affinity of the antagonist for the NK-1R relative to its affinity for either the NK-2 receptor or the NK-3 receptor. NK-1R antagonists include but are not limited to the compounds maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant and vestipitant.

SARS-CoV-2 and COVID-19 disease

[0026] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes serious respiratory illness (including pneumonia and lung failure) which has been termed coronavirus disease 2019 (COVID-19). Within a few months of the first report of SARS- CoV-2 infection in Wuhan, China, the virus has spread worldwide, reaching a pandemic level in months. COVID-19 has caused a large number of human casualties. Development of strategies to treat the infected and contain the virus's spread are urgently needed. Likewise, severe acute respiratory syndrome coronavirus (“SARS-CoV” or “SARS”) is a viral respiratory disease that was first reported in Asia in February 2003 and quickly spread to about two dozen countries, and Middle East respiratory syndrome coronavirus (“MERS- CoV” or “MERS”) is a viral respiratory disease that was first reported in Saudi Arabia in 2012 and has since spread to more than 27 other countries. The methods as disclosed herein can be applied to methods of treatment for COVID-19, SARS, MERS-CoV, and/or other b-coronaviruses.

[0027] Repurposing of existing drugs for b-coronavirus infection including SARS-CoV-2 has the benefit of reduced cost, safety, and expedited time to clinic. Several studies indicate that both DNA and RNA viruses (e.g., respiratory syncytial virus, measles virus, and varicella zoster virus (VZV)) use the NK-1R to promote viral spread (Figure 2). The VZV glycoprotein B (gB) contains a 4 amino acid sequence (Phe-Phe-Gly-Leu; SEQ ID NO: 2), homologous to NK-IR’s endogenous ligand substance P (SEQ ID NO: 1), that binds with high affinity to NK-1R (Figure 1A). This 4 amino acid sequence dictates the affinity for active NK-1R binding; the tri-peptide sequence Phe-Phe-Gly has also been shown to be sufficient for NK-1R binding, albeit, at a lower affinity (e.g., measles virus, Figure IB). VZV gB binding to NK-1R leads to transcriptional changes in the host cell that promote viral spread, including inhibition of the antiviral interferon-gamma (IFN-g) immune response. It has been shown that treatment with aprepitant, an NK-1R antagonist which is already in clinical use as an anti-emetic, inhibited viral spread and restored the host cell’s ability to mount an antiviral IFN-g immune response to clear virus (Figure 3). SARS-CoV- 2 ORF la/b protein also expresses a homologous 4 amino acid sequence (Tyr-Phe-Gly-Leu (SEQ ID NO: 4); the Tyr residue is a conservative substitution for Phe), and this protein is essential for vims replication (Figure 1A). The Tyr is a conserved amino acid substitution, such that a Tyr in place of a Phe will have the same action (they have very similar properties, including the important aromatic ring). This has been shown in studies showing receptor binding kinetics, however this has not ever been proposed or studied for the specific viruses detailed herein. NK-1R antagonists, such as aprepitant, may be used to inhibit ORF la/b protein from binding to NK-1R. Such an interaction can be confirmed using a synthetic peptide including regions of ORF la/b with NK-1R binding sites.

[0028] In addition, identification of biomarkers that predict the severity of b-coronavirus infection, including SARS-CoV-2 infections and/or COVID-19 disease can assist clinicians in patient triage and care. For example, SARS-CoV-2 spike protein has substance P homologous regions that may bind host NK-1R for entry/spread (as in VZV) and mouse coronavirus induces IL-25 in lung leading to aberrant inflammation (mediated in part by TRPM5).

[0029] Further, identification of pathways that can be targeted by repurposed drugs to treat b-coronavirus infection, including SARS-CoV-2 infection and COVID-19 disease can assist clinicians in patient care.

Pathogen-induced immunosuppression

[0030] During infection, pathogens secrete a variety of soluble factors that suppress the ability of surrounding cells to elicit immune responses that would otherwise clear the pathogens and/or prevent their spread. For example, a mechanism common to many pathogens is the suppression of the host’s interferon (IFN) responses. It would be untenable to attempt to therapeutically block each soluble factor produced by each type of pathogen, so it is advantageous to instead block the host’s signaling response. Specifically, as disclosed herein, blocking the NK-1R via administration of a composition comprising an NK-1R antagonist can slow or prevent pathogen- induced immunosuppression.

[0031] The discovery of NK-1R as a target for inducing the host to mount an immune response provides a safe, novel approach for antimicrobial treatments. Of note, the compositions disclosed herein do not induce the IFN response directly, but rather prevent the pathogen-induced suppression of this response. This means that these compositions only have effect in the presence of a pathogen/pathogen alarm signal and will not stimulate an IFN response in the absence of infection, thus minimizing inappropriate proinflammatory immune responses.

[0032] Although the scope of the claims of this disclosure are not to be limited by potential mechanisms of action, the therapeutic benefits of the pharmaceutical compositions of the disclosure, when administered in accordance with the teachings herein, are believed to arise at least in part from the biological effects of blocking the NK-1R in a therapeutically effective manner. As the NK-1R is expressed on neurons, brainstem, vascular endothelial cells, muscle, gastrointestinal tracts, genitourinary tract, pulmonary tissue, thyroid gland and different types of immune cells, administration of therapeutically effective doses of the pharmaceutical compositions of the disclosure generally will have a systemic effect. [0033] In certain embodiments, provided herein are methods of treating or otherwise providing a beneficial effect to a subject having or at risk of b-coronavirus infection such as SARS-CoV-2 infection and/or COVID-19 disease and/or pathogen-induced immunosuppression. Non-limiting examples of beneficial effects include reducing, decreasing, inhibiting, ameliorating or preventing onset, severity, duration, progression, frequency or probability of infection and/or one or more symptoms or pathologies associated with b-coronavirus infection, including SARS-CoV-2 infection and/or COVID- 19 disease.

[0034] Accordingly, the present disclosure provides methods and pharmaceutical compositions relating to the immune system’s response to b-coronavirus infection, including SARS-CoV-2 infection.

[0035] Those of skill in the art will appreciate upon contemplation of the disclosure herein that the pharmaceutical compositions of the disclosed methods relating to NK-1R antagonists are generally useful in treating disease. Thus, whereas this disclosure provides a significant advance in the development of better treatments for such diseases, particularly in preventing, treating, and ameliorating the symptoms and risks of b-coronavirus infection including SARS-CoV-2 infection and/or COVID-19 disease, these same compositions and treatments are useful in many other settings, including in treating SARS, MERS, and/or other coronaviral infections.

[0036] Specific NK-1R antagonists for use in the presently disclosed methods, and pharmaceutical formulations including them, include but are not limited to maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, vestipitant, tradipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant, and combinations thereof.

[0037] Those of skill in the art will appreciate that the pharmaceutical compositions of the methods of this disclosure may be administered via a variety of routes on a variety of dosing schedules. For example, the NK-1R antagonist composition can be administered to a subject by any of a variety of methods known in the art, although for many therapeutic applications, the route/mode of administration is subcutaneous injection, intravenous injection or infusion. Administration can be systemic or local. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. For example, pharmaceutical compositions containing the NK-1R antagonist may be formulated for administration to a subject by parenteral, intradermal, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, oral, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal.

[0038] A suitable dosage for the NK-1R antagonists in the diseases as disclosed herein can be selected by the person of skill in the art with reference to clinical indicators. Dosing schedules will typically include no more than one to five administrations per day or per week. Typically, the longer the duration of continuous administration, the fewer number of doses are administered per week. Often, only one dose per week will be administered. Other dosing schedules can be effective. For example, dosing may continue for longer or shorter than 8 weeks, and there can be “drug holidays” in which one or more administrations in a cycle of administrations is omitted.

[0039] Although the amount of the NK-1R antagonist in the composition may vary according to a host of factors, a suitable dosage range may be, for example 20 mg/day to 175 mg/day, or 40 mg/day to 125 mg/day. For example, a suitable dosage may be 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 175 mg, 180 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 275 mg, 280 mg, 300 mg, 325 mg, 350 mg, 375 mg, or 400 mg. In another example, a suitable dosage may be 125 mg on the first day and 80 mg each day thereafter. In other embodiments, a suitable dosage range may be determined based on the subject’s body weight, for example 0.1 mg/kg to 50 mg/kg of the subject's body weight, or 0.5 mg/kg to 10 mg/kg of the subject's body weight, or 1 mg/kg to 5 mg/kg of the subject's body weight. These ranges provide, for example, a therapeutically effective amount of the NK-1R antagonist.

[0040] Those of skill in the art will understand that for administration, the NK-1R antagonist can be incorporated into a pharmaceutical composition suitable for administration to a subject. Such a pharmaceutical composition comprises at least one NK- 1R antagonist and a pharmaceutically acceptable carrier, solubilizer, emulsifier, preservative and/or adjuvant excipient or diluent. The NK-1R antagonist composition may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including polymers, implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, poly anhydrides, polyglycolic acid, collagen, poly orthoesters, and polylactic acid. The disclosed formulations may include solvents (aqueous or non-aqueous), solutions (aqueous or non-aqueous), emulsions (for example, oil-in-water or water- in-oil), suspensions, syrups, elixirs, dispersion and suspension media, coatings, isotonic and absorption promoting or delaying agents, compatible with pharmaceutical administration or in vivo contact or delivery. Pharmaceutically advantageous formulation materials are nontoxic to recipients at the dosages and concentrations employed. The pharmaceutical composition may contain one or more various formulation materials for modifying, maintaining or preserving the composition or properties of the composition, for example, the color, consistency, isotonicity, odor, osmolarity, pH, sterility, stability, viscosity and other properties. In any of the treatment methods of this disclosure, it is contemplated that additional therapies may be co administered, where beneficial to the patient. Such therapies may be used in combination with the methods and agents of this disclosure in a variety of settings.

Exemplary Embodiments

[0041] Among the embodiments provided herein are:

1. A method for treating SARS-CoV-2 infection and/or COVID-19 disease, or preventing or minimizing onset or progression of COVID-19 disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an NK-1R antagonist.

2. The method of embodiment 1, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant, or a combination thereof.

3. The method of embodiment 1, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant, or a combination thereof.

4. The method of embodiment 1 or 2, wherein the method inhibits the onset or progression of COVID-19 disease in the subject.

5. The method of any one of embodiments 1 to 3, wherein the therapeutically effective amount of the NK-1R antagonist administered to the subject is 20 mg/day to 375 mg/day.

6. The method of any one of embodiments 1 to 4, wherein the NK-1R antagonist is administered to the subject orally.

7. The method of any one of embodiments 1 to 5, wherein the method reduces the onset or progression of COVID-19 disease in the subject and/or provides the subject with protection against SARS-CoV-2 infection or pathogenesis.

8. The method of any one of embodiments 1 to 6, wherein the treatment decreases susceptibility to, or inhibits, SARS-CoV-2 infection in the subject.

9. The method of any one of embodiments 1 to 7, wherein the NK-1R antagonist is administered prior to, concurrently with, or following infection of the subject with SARS- CoV-2, exposure to or contact of the subject with SARS-CoV-2, or following development of a symptom or pathology of acute or chronic SARS-CoV-2infection.

10. A composition comprising an NK-1R antagonist for use in a method for treating SARS-CoV-2, COVID-19 disease, and/or pathogen-induced immunosuppression.

11. The composition of embodiment 9, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant or a combination thereof.

12. A composition comprising a TRPM5 antagonist for use in a method for treating SARS-CoV-2, COVID-19 disease, and/or pathogen-induced immunosuppression.

13. A method for treating a b-coronavirus infection and/or related disease, or preventing or minimizing onset or progression of b-coronavirus related disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an NK-1R antagonist. 14. The method of embodiment 12, wherein the b-coronavirus is SARS-CoV-2, SARS, or MERS-CoV.

15. The method of embodiment 12 or 13, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant or a combination thereof.

16. The method of any one of embodiments 12 to 14, wherein the method inhibits the onset or progression of disease in the subject.

17. The method of any one of embodiments 12 to 15, wherein the therapeutically effective amount of the NK-1R antagonist administered to the subject is 20 mg/day to 375 mg/day.

18. The method of any one of embodiments 12 to 16, wherein the NK-1R antagonist is administered to the subject orally.

19. The method of any one of embodiments 12 to 17, wherein the method reduces the onset or progression of disease in the subject and/or provides the subject with protection against b-coronavirus infection or pathogenesis.

20. The method of any one of embodiments 12 to 18, wherein the treatment decreases susceptibility to, or inhibits, b-coronavirus infection in the subject.

21. The method of any one of embodiments 12 to 19, wherein the NK-1R antagonist is administered prior to, concurrently with, or following infection of the subject with b- coronavirus, exposure to or contact of the subject with a b-coronavirus infection, or following development of a symptom or pathology of acute or chronic b-coronavirus infection.

22. A composition comprising an NK-1R antagonist for use in a method for treating SARS-CoV-2, COVID-19 disease, SARS, MERS-CoV, and other b-coronaviruses and/or pathogen-induced immunosuppression.

23. The composition of embodiment 21, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant or a combination thereof.

EXAMPLES

[0042] The materials, methods, and embodiments described herein are further defined in the following Examples. Certain embodiments are defined in the Examples herein. It should be understood that these Examples, while indicating certain embodiments, are given by way of illustration only. From the disclosure herein and these Examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

[0043] EXAMPLE 1: Determination if peptides from SARS-CoV-2 ORFla/b that contain substance P-homologous regions bind to NK-1R and if binding can be blocked by NK-1R antagonist, aprepitant.

[0044] In this example, three peptides containing regions of ORF la/b with NK-1R binding sites and a peptide spanning a region without NK-1R binding sites will be synthesized. (FIGURE 1A). As a positive control, a calcium fluorophore will be added to primary human lung fibroblasts (HFLs) then substance P (subP) applied to show calcium influx into the cell mediated by subP binding to NK-1R (Bubak et ah, 2018); aprepitant will be added in a parallel experiment to show that it blocks subP binding and calcium influx by microscopy. In a similar experiment, the 4 synthetic peptides will each separately be added to calcium fluorophore-treated HFLs with and without aprepitant to determine their ability to bind NK-1R. These results will provide proof-of-concept data that SARS-CoV-2 uses NK-1R for pathogenesis, and provide the foundation for clinical trials and future research using the whole viral protein/vims.

[0045] EXAMPLE 2: Identification of pathways in COVID-19 samples that can be targeted by repurposed drugs to inhibit viral spread and that serve as prognostic biomarkers. [0046] Using BioSpyder’s TempO-Seq technology, which allows high throughput, 3-day whole-human transcriptome sequencing of fixed biological samples, 24 COVID-19 patient PBMCs and BALs/oral swabs/tissue (48 samples total) will be sequenced and compared to 24 control patient PBMCs and BALs/oral swabs/tissue (48 samples total). Pathway analyses will be completed to identify potential therapeutic targets and validate the two repurposed drugs (neurokinin- 1 receptor (NK-1R) and TRPM5 antagonists) as well as to identify individual transcript/pathways that can serve as biomarkers for severity of infection when correlated with clinical status.

[0047] EXAMPLE 3: Identification of pathways in COVID-19 samples [0048] NFAT (nuclear factor of activated T-cells) controls the expression of interferon gamma (IFNy), a key regulator in the appropriate control of immune function (Vaeth and Feske, 2018, “NFAT control of immune function: New Frontiers for an Abiding Trooper”. FlOOORes. 7:260). Many viruses exploit this pathway to evade the immune system. To examine this in COVID-19, whole-blood RNA sequencing of 66 COVID-19 patients and was performed and compared to controls. The data are shown in the Table 1.

[0049] The preliminary data from the whole-blood RNA sequencing of 66 COVID-19 patients suggests that the SARS-CoV-2 virus also suppresses this pathway. We found, compared to controls, a significant reduction in the gene pathways “Role of NFAT in Regulation of the Immune Response”, “Neuroinflammation Signaling Pathway”, and “Natural Killer Cell Signaling”, “Production of Nitric Oxide and Reactive Oxygen Species in Macrophages,” as well as a trending down pathway of “Role of PKR in Interferon

Induction and Antiviral Response”.

TABLE 1

Overall, these data suggest that restoring this interferon/anti- viral response could serve as a potential therapeutic target for SARS-CoV-2 infections.

Claims

2. The method of claim 1, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant, or a combination thereof.

3. The method of claim 1 or 2, wherein the method inhibits the onset or progression of COVID-19 disease in the subject.

4. The method of any one of claims 1 to 3, wherein the therapeutically effective amount of the NK-1R antagonist administered to the subject is 20 mg/day to 375 mg/day.

5. The method of any one of claims 1 to 4, wherein the NK-1R antagonist is administered to the subject orally.

6. The method of any one of claims 1 to 5, wherein the method reduces the onset or progression of COVID-19 disease in the subject and/or provides the subject with protection against SARS-CoV-2 infection or pathogenesis.

7. The method of any one of claims 1 to 6, wherein the treatment decreases susceptibility to, or inhibits, SARS-CoV-2 infection in the subject.

8. The method of any one of claims 1 to 7, wherein the NK-1R antagonist is administered prior to, concurrently with, or following infection of the subject with SARS- CoV-2, exposure to or contact of the subject with SARS-CoV-2, or following development of a symptom or pathology of acute or chronic SARS-CoV-2infection.

9. A composition comprising an NK-1R antagonist for use in a method for treating SARS-CoV-2, COVID-19 disease, and/or pathogen-induced immunosuppression.

10. The composition of claim 9, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant or a combination thereof.

11. A composition comprising a TRPM5 antagonist for use in a method for treating SARS-CoV-2, COVID-19 disease, and/or pathogen-induced immunosuppression.

12. A method for treating a b-coronavirus infection and/or related disease, or preventing or minimizing onset or progression of b-coronavirus related disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an NK-1R antagonist.

13. The method of claim 12, wherein the b-coronavirus is SARS-CoV-2, SARS, or MERS-CoV.

14. The method of claim 12 or 13, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant or a combination thereof.

15. The method of any one of claims 12 to 14, wherein the method inhibits the onset or progression of disease in the subject.

16. The method of any one of claims 12 to 15, wherein the therapeutically effective amount of the NK-1R antagonist administered to the subject is 20 mg/day to 375 mg/day.

17. The method of any one of claims 12 to 16, wherein the NK-1R antagonist is administered to the subject orally.

18. The method of any one of claims 12 to 17, wherein the method reduces the onset or progression of disease in the subject and/or provides the subject with protection against b-coronavirus infection or pathogenesis.

19. The method of any one of claims 12 to 18, wherein the treatment decreases susceptibility to, or inhibits, b-coronavirus infection in the subject.

20. The method of any one of claims 12 to 19, wherein the NK-1R antagonist is administered prior to, concurrently with, or following infection of the subject with b- coronavirus, exposure to or contact of the subject with a b-coronavirus infection, or following development of a symptom or pathology of acute or chronic b-coronavirus infection.

21. A composition comprising an NK-1R antagonist for use in a method for treating SARS-CoV-2, COVID-19 disease, SARS, MERS-CoV, and other b-coronaviruses and/or pathogen-induced immunosuppression.

22. The composition of claim 21, wherein the NK-1R antagonist comprises maropitant, casopitant, aprepitant, netupitant, fosaprepitant, lanepitant, befetupitant, rolapitant, tradipitant, vestipitant, befetupitant, ezlopitant, L-733,060 (Merck), orvepitant, serlopitant, vofopitant or a combination thereof.